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| United States Patent |
6,214,374
|
|
Schmirler
, et al.
|
April 10, 2001
|
Compositions, methods and devices for the transdermal delivery of drugs
Abstract
The present invention is directed to compositions, and methods for the
delivery of drugs. Devices for the transdermal delivery of drugs are also
provided. Specifically, the present invention relates to hydrogel
compositions comprising water and a base mixture, in which the base
mixture comprises: (i) a gelling agent consisting of methycellulose or at
least one natural gum, or a mixture thereof; (ii) at least one natural
gum: (iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi)
sodium chloride.
The compositions may further comprise pectin, glycolic, alcoholic or
oil-based additives, a coloring, fragrance, or other pharmaceutically
acceptable additive. The compositions may further comprise substituted
ureas of the formula R--NH--CO--NH.sub.2 such as butylurea. The
compositions may further comprise drugs such as hormones selected from
progesterone, progestin, estrogen and testosterone. Methods for the
treatment of disorders responsive to hormone therapy are also provided.
| Inventors:
|
Schmirler; Dennis Lee (2112 Baypoint La., Hartland, WI 53029);
Portman; Edward Malcolm (659 Peachtree St., Suite 224, Atlanta, GA 30308);
Christensen; Michael S. (215 Springhouse La., Merion, PA 19066)
|
| Appl. No.:
|
652280 |
| Filed:
|
May 22, 1996 |
| Intern'l Class: |
A61K 009/70 |
| Field of Search: |
424/430,443,455,484,449
|
References Cited
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|
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|
| Foreign Patent Documents |
| 93/10163 | May., 1993 | WO.
| |
Other References
Barry and Bennett, "Effect of Penetration Enhancers on the Permeation of
Mannitol, Hydrocortisone, and Progesterone Through Human Skin," J. Pharm.
Pharmacol. 39:535-546 (1987).
Chakmakjan et al., "Biovailability of Progesterone with Different Modes of
Administration," The Journal of Reproductive Medicine 32(6):443-447 (Jun.
1987).
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Future, 13(4):343-362 (1988).
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Derivatives," Arch. Pharm. Res. 14(1):12-18 (1991).
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Applications," CRC Press, Inc., pp. 95-108 and 151-176 (1987).
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Press, Inc., pp. 65-94 and 115-160 (1987).
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Delivery Systems: Part II: System Design Considerations," Pharmaceutical
Technology, pp. 55-59 (Oct. 1990).
Pfister, "Customizing Silicone Adhesives for Transdermal Drug Delivery
Systems," Pharmaceutical Technology, p. 126 (Mar. 1989).
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45:334-346 (1965).
Sitruk-Ware, "Transdermal Application of Steroid Hormones for
Contraception," J. Steroid Biochem. Molec. Biol. 53(1-6):247-251 (1995).
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Sun. Med. 25:77-82 (1993).
Sitruk-Ware, "Transdermal Delivery of Steroids," Contraception 39(1):1-20
(Jan. 1989).
Sitruk-Ware, "Innovative Technology for Hormonal Replacement Therapy,"
Maturitas 10:79-81 (1988).
Toddywala et al., "Evaluation of Silicone-Based Pressure Sensitive
Adhesives for Transdermal Drug Delivery. I. Effect of Pentrant
Hydrophilicity." J. Controlled Release 14:29-41 (1990).
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of Drugs from Hydrogels," Pharmazie 39(9):618-320 (1984).
|
Primary Examiner: Clardy; S. Mark
Assistant Examiner: Shelborne; Kathryne E.
Attorney, Agent or Firm: Andrus, Sceales, Starke & Sawall, LLP
Claims
What is claimed is:
1. A composition consisting essentially of:
(a) 3-12% of a base mixture consisting essentially of: 50-80% (by weight)
methyl cellulose, 15-25% of a natural gum selected from the xanthin and
guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3% methylparaben, 1-3%
sodium chloride and 0.75-3.5% pectin;
(b) 0.5-15% by weight of a substituted urea of the formula
R--NH--CO--NH.sub.2, wherein R is hydrogen, hydroxyl or lower alkyl having
from 1 to 8 carbon atoms selected from the group consisting of methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl,
heptyl and octyl;
(c) 5-20% by weight of a hormone selected from the group consisting of
progesterone, progestin, estrogen, and testosterone, or a mixture of any
two or more of the foregoing;
(d) 0-20% by weight propylene glycol; and
(e) 20-80% by weight water;
in which said base mixture and water form a hydrogel.
2. A composition consisting essentially of:
(a) about 9% by weight of a base mixture consisting essentially of: about
63% (by weight) methyl cellulose, about 21% guar gum, about 5% glucose,
about 3.5% propylparaben, about 3% methylparaben, about 1.5% sodium
chloride and about 3% pectin;
(b) about 2% by weight of a substituted urea of the formula:
R--NH--CO--NH.sub.2, wherein R is hydrogen, hydroxyl or lower alkyl having
from 1 to 8 carbon atoms selected from the group consisting of methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl,
heptyl and octyl;
(c) about 10% by weight of progesterone;
(d) about 20% by weight propylene glycol; and
(e) 59% by weight water; in which said base mixture and water form a
hydrogel.
3. A composition consisting essentially of:
(a) about 9% by weight of a base mixture consisting essentially of: about
63% (by weight) methyl cellulose, about 21% guar gum, about 5% glucose,
about 3.5% propylparaben, about 3% methylparaben, about 1.5% sodium
chloride and about 3% pectin;
(b) about 2% by weight butylurea;
(c) about 10% by weight of progesterone;
(d) about 20% by weight propylene glycol; and
(e) about 59% by weight water;
in which said base mixture and water form a hydrogel.
4. A composition consisting essentially of:
(a) a base mixture consisting essentially of methyl cellulose, guar gum,
glucose, propylparaben, methyl paraben, sodium chloride and pectin;
(b) butylurea
(c) progesterone
(d) propylene glycol; and
(e) water;
in which said base mixture and water from a hydrogel.
5. A method of treating or preventing a condition responsive to hormone
replacement therapy comprising placing a composition of claim 1 or 2, said
composition comprising a therapeutically effective amount of said hormone
or mixture of hormones, in contact with the skin of a subject in need of
such treatment.
6. The method of claim 5 wherein said condition is selected from the group
consisting of premenstrual syndrome, menopause, infertility, osteoporosis,
dysfunctional bleeding, corpus luteum failure, senile vulvo-vaginitis, and
hypogonadism.
7. A method of providing contraception to a male or female subject
comprising placing a composition of claim 1 or 2, said composition
comprising a therapeutically effective amount of said hormone or mixture
of hormones, in contact with the skin of a subject in need of
contraception.
8. The method of claim 7 wherein said subject is female and said hormone or
mixture of hormones is selected from the group consisting of progesterone,
progestin, estrogen, and a mixture of any two or more of the foregoing.
9. The method of claim 8 wherein said hormone is a mixture of one or more
estrogens and one or more protesting.
10. The method of claim 8 wherein said hormone is a mixture of progesterone
and one or more estrogens.
11. The method of claim 8 wherein said hormone is selected from the group
consisting of progesterone and progestins.
12. The method of claim 7 wherein said subject is a male and said hormone
is testosterone.
13. A method of delivering a therapeutically effective amount of a hormone
or mixture of hormones to the bloodstream of a subject comprising
contacting the skin of said subject with a composition of claim 1 or 2
comprising a therapeutically effective amount of said hormone or mixture
of hormones.
14. A method for treating vaginal yeast infection comprising placing a
composition of claim 1 or 2 inside the vagina of a female subject
suffering from yeast infection.
15. A method for providing contraception to a female subject comprising
placing a composition of claim 1 or 2 inside the vagina of a female
subject in need of contraception.
16. A method for treating vaginal dryness comprising placing a composition
of claim 1 or 2 inside the vagina of a female subject suffering from
vaginal dryness.
17. A method for vaginal delivery of a drug comprising placing a
composition of claim 1 or 2 inside the vagina of a female subject.
Description
1. INTRODUCTION
The present invention relates to compositions for the transdermal delivery
of hormones comprising a hydrogel-forming base mixture and a skin
permeation enhancer. Methods for the treatment of disorders responsive to
the administration of hormones are also provided. The present invention
further relates to devices for the transdermal delivery of drugs.
2. BACKGROUND
A recent trend in the pharmaceutical industry has been the development of
new drug delivery systems for both old and new drugs. Much of the current
research in drug delivery technology is aimed at developing formulations
and devices that improve the therapeutic effectiveness of drugs over
conventional means of administration by controlling the rate, time and
place of release of drugs in the body.
Conventional dosage types include sublingual (under the tongue), oral
(capsules, tablets, liquids), injectable, nasal and parenteral
(suppository and non-oral) forms. While oral dosage forms comprise a
substantial majority of all present dosage forms and offer ease of
administration and low cost-per-use, they can suffer from inconvenient
dosing intervals, side effects and reduced efficacy. Conventional dosage
forms have disadvantages in certain patients, including unpredictable
blood levels, difficult or uncomfortable administration and poor
compliance. In order to maintain optimum blood levels, some conventional
forms of drug delivery require frequent doses which can be difficult to
remember or understand, particularly for the elderly patient. Failure to
comply with a recommended drug regimen can endanger a patient's health.
Controlled drug delivery systems have been introduced within the last
decade to eliminate or reduce the limitations of conventional dosage
forms. One type of controlled delivery is transdermal delivery, which
involves delivery of a therapeutic agent through the skin for distribution
within the body by the circulation of the blood. Transdermal delivery can
be compared to continuous, controlled intravenous delivery of a drug using
the skin as a port of entry instead of an intravenous needle. The
therapeutic agent passes through the outer layers of the skin, diffuses
into the capillaries, or tiny blood vessels in the skin, and then is
transported into the main circulatory system.
Examples of drugs which have successfully been delivered transdermally
include scopolamine for the treatment of motion sickness, nitroglycerin
for the treatment of angina, estrogen and combined estrogen/progestogen
for menopausal symptoms and osteoporosis, isosorbide dinitrate for angina,
clonidine for hypertension, nicotine for smoking cessation, fentanyl for
pain management and testosterone for male hypogonadism.
The hormone progesterone is used in the treatment of premenstrual syndrome,
menopausal hormone replacement therapy (in combination with estrogen),
infertility and a variety of gynecological conditions. The transdermal
delivery of progesterone has been reported. However, due to the large size
of the progesterone molecule, efforts to transdermally deliver
progesterone in therapeutically effective amounts have often been
unsuccessful. Progesterone is known to be metabolized within the skin by
the 5-.alpha.-reductase enzyme which converts it to inactive
5-.alpha.-dihydroxyprogesterone (R. Sitruk-Ware, 1995, "Transdermal
Application of Steroid Hormones for Contraception," J. Steroid Biochem.
Molec. Biol. 53 (1-6):247-251). Thus, relatively high, multiple doses are
required to elicit the desired progestational effect. The desired goal of
transdermal delivery of progesterone is to be able to maintain consistent
serum levels of progesterone at relatively low dosage levels without
requiring multiple dosing.
Low rates of transdermal delivery of progesterone have been reported by
various researchers. For example, Guy et al. (1987, "Kinetics of Drug
Absorption Across Human Skin In Vivo," Pharmacol. Skin 1:70-76), disclose
that about 1.2 .mu.g/cm.sup.2 penetrated in a 24-hour period, when the
drug was applied as a thin film on the skin in vivo. Barry and Bennett,
(1987, "Effect of Penetration Enhancers on the Permeation of Mannitol,
Hydrocortisone, and Progesterone Through Human Skin," J. Pharm. Pharmacol.
39:535-546), report a rate of 0.477 .mu.g/cm.sup.2 /hour in vitro through
excised human skin. Both Guy et al. and Barry and Bennett measured
penetration through the skin after progesterone was applied in an acetone
solution, the solvent was allowed to evaporate, and the skin surface was
hydrated, either by occlusion or by application of a small amount of
water. Barry and Bennett reported higher rates of transdermal penetration
of progesterone when penetration enhancers were applied to the skin
following application of the acetone/progesterone solution and evaporation
of the solvent. Rates of 11.4 (+/-4.6) and 12.4 (+/-4.4) .mu.g/cm.sup.2
/hour, respectively, were observed after application of 2-pyrrolidone and
N-methylformamide permeation enhancers. However, neither the methods nor
the solvent vehicles for application of progesterone to the skin disclosed
by these references are appropriate or practical for use in a transdermal
patch delivery system, for number of reasons. Application of acetone to
the skin commonly results in skin irritation, an effect that may also be
encountered with 2-pyrrolidone and N-methylformamide. Further, permeation
enhancers such as 2-pyrrolidone and N-methylformamide may impose health
risks. Also, the volatile solvent carriers disclosed by these references
can be difficult and impractical to incorporate into a patch system.
The transdermal delivery of progesterone, progestins, estrogens and
testosterone from gel-like matrices has been reported. R. Sitruk-Ware
(1988, "Innovative Technology for Hormonal Replacement Therapy,"
Maturitas, 10:79-81) discloses a progesterone cream for use as a topical
therapy in benign breast diseases. R. Sitruk-Ware (1989, "Transdermal
Delivery of Steroids," Contraception 39, (1):1-20) discloses that only
small amounts of progesterone can be obtained in plasma via skin
penetration, but when applied on the breast, high amounts of progesterone
can be obtained in the breast tissue. A five-fold increase in progesterone
concentration was demonstrated in breast tissue of women treated topically
with the steroid dissolved in an alcohol/water gel.
Compounds that act as permeation enhancers have been added to transdermal
drug delivery systems for a number of drugs, including progesterone.
Pfister and Hsieh (1990, in "Permeation Enhancers with Transdermal Drug
Delivery Systems: Part II: System Design Considerations," Pharmaceutical
Technology, October 1990: 55-60), disclose a wide variety of permeation
enhancers. For example, isopropyl palmitate and isopropyl myristate are
disclosed as cosolvents to enhance the solubility of nitroglycerin in a
polymer matrix-type transdermal system, which in turn optimizes the
release of the drug from the system. Similarly, ethanol is disclosed as
enhancing the solubility of 17-.beta.-estradiol in the reservoir
compartment of a transdermal drug delivery device. Other skin penetration
enhancers are disclosed, including stearyl alcohol, glycerol,
2-pyrrolidone, urea, propylene glycol, oleic acid, and palmitic acid. D.
R. Friend (1990, "Transdermal Delivery of Contraceptives", Critical
Reviews in Therapeutic Drug Carrier Systems 7 (2):149-186), discloses
dimethyl sulfoxide, N,N-dimethyl acetamide, N,N-dimethyl formamide,
2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,
1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone,
2-pyrrolidone-5-carboxylic acid, N,N-dimethyl-m-toluamide, urea, ethyl
acetate, 1-dodecylazacycloheptan-2-one (azone), oleic acid and ethanol as
permeation enhancers. Butylurea has also been disclosed as a permeation
enhancer. For example, U.S. Pat. No. 5,128,376 discloses a method for
percutaneous administration of a drug from a mixture of an adjuvant, a
solvent and a diol/triol moderator, wherein the solvent, which enhances
permeation, may be a substituted urea such as butylurea. U.S. Pat. No.
4,863,952 discloses an improved method of drug administration using a
mixture comprising pyrrolidone carboxylic acid esters as percutaneous
promoters, and optionally, substituted ureas such as butylurea. S. K. Han
et al. (1991, "Percutaneous Absorption-Enhancing Activity of Urea
Derivatives," Arch. Pharm. Res. 14(1):12-18) disclose the use of urea
derivatives, including butylurea, to enhance the percutaneous absorption
of salicylic acid and sodium salicylate from a vaseline base.
Hydrogels are well known in the art as vehicles for the controlled release
of drugs. N. A. Peppas, ed., "Hydrogels in Medicine and Pharmacy," CRC
Press, Inc. (1987) Vol. II, discloses the use of water soluble cellulose
ethers such as methylcellulose for controlled release drug delivery
systems. Volume III of the same publication discloses the release of
progesterone from rod-shaped monolithic hydrogel devices.
U.S. Pat. Nos. 5,344,655 and 5,254,338 disclose that hydrogel bases
containing water soluble polymers such as cellulose derivatives are known
in the art for delivery of drugs through the skin. U.S. Pat. No. 4,693,887
discloses hydrogel compositions for the controlled release of
contraceptives such as progesterone. The hydrogels are blends of either
N-vinyl lactam or a copolymer of N-vinyl lactam and may further comprise
spermicides such as urea. U.S. Pat. No. 5,405,366 discloses an adhesive
hydrogel comprising an aqueous mixture of a radiation crosslinkable
water-soluble polymer such as a polymer of N-vinyl-2-pyrrolidone and
ethylene oxide and a humectant such as propylene glycol which may be used
in a transdermal drug delivery system. The hydrogel may also contain
preservatives such as propyl paraben and methyl paraben. U.S. Pat. No.
4,593,053 discloses a skin-compatible pressure-sensitive adhesive hydrogel
comprising polyvinyl pyrrolidone and polyvinyl alcohol, a polar
plasticizer or humectant such as propylene glycol, water and a drug. The
composition may also contain cellulose derivatives to increase strength
and guar gum to increase tackiness.
The transdermal delivery of progesterone, progestins, estrogens and
testosterone from hydrogel matrices comprising permeation enhancers is
also known. For example, U.S. Pat. No. 5,030,629 discloses transdermal
formulations containing progesterone, ethanol, saline and an imidazoline
penetration enhancer. Dosage forms of the formulations for application to
the skin include gels, which may comprise inert carriers such as propylene
glycol, urea and methylcellulose. U.S. Pat. No. 5,362,497 discloses
compositions for transdermal delivery of, inter alia, androgens such as
testosterone and estrogens such as estradiol comprising water- and
fat-soluble absorption enhancers, and a water-absorbent resin such as a
vinyl acetate-acrylic acid ester copolymer that swells to form a hydrogel
upon contact with water. U.S. Pat. No. 5,064,654 discloses a transdermal
drug formulation comprising a drug such as progesterone or estradiol,
water and ethanol. The formulation may also contain an adhesive or gelling
agent such as pectin, guar gum or methyl cellulose. U.S. Pat. No.
4,942,158 discloses a composition comprising a combination of isopropyl
alcohol and isobutyl alcohol to enhance the transdermal penetration of
steroids such as estradiol, or a combination of estradiol with a
progestogen. The composition may also include water and a gelling agent
such as methyl cellulose. U.S. Pat. No. 4,865,848 discloses compositions
for enhancing the transdermal delivery of drugs, including progesterone,
comprising sucrose esters as penetration enhancers. Preferably, the
permeation enhancer and the drug are dispersed in a matrix which may be a
gel or a hydrophilic polymer.
Despite their advantages, conventional transdermal delivery systems have
been limited due to barrier properties of the stratum corneum, the skin's
protective outer layer. Large, high molecular weight drugs such as
progesterone are difficult to deliver through the skin in effective
amounts. In general, the skin is highly resistant to permeation by
chemicals, including drugs. Although the skin is only a few millimeters
thick, the stratum corneum serves as a highly protective barrier against
physical, chemical and bacterial penetration. This barrier primarily
consists of dead skin cells bound together by certain fatty (lipid)
materials. Generally, only drugs that are effective in the body at very
low concentrations or that have particular physical properties have been
successfully delivered through the skin in therapeutically effective
amounts. High molecular weight drugs and drugs which are either charged or
highly polar remain difficult to administer transdermally.
Natural progesterone, which is the form of progesterone that is produced by
the body, has been administered in oral, injectable and suppository forms.
The disadvantages of injectable and suppository forms are obvious: they
are burdensome to administer. The disadvantage of oral forms is that they
are short acting, and to maintain adequate blood levels, they have to be
dosed throughout the day. The bulk of orally administered progesterone is
metabolized by the digestive system and excreted before it can be used by
the body. In fact, progesterone, whether administered orally, vaginally or
rectally, has a half life in the body of only about 2.2 hours. Therefore,
much larger amounts than the body actually requires must be dosed to
maintain effective blood levels.
To address the problems associated with conventional means of
administration of natural progesterone, a variety of synthetic forms,
known as progestins, have been developed. Progestins fall primarily into
two categories. The first group, pregnanes, is derived from
17-.alpha.-acetoxy progesterone. A classic example is medroxy progesterone
acetate (Provera). With an increased affinity for progesterone receptors,
these compounds have marked progestational activity. They possess
anti-estrogenic anti-gonadotropic, and no significant androgenic
properties. A second group, estranes, derived from
17-.alpha.-ethinyl-1-nortestosterone, includes norethindrone acetate
(aygestin). Besides progestational activity, these compounds have marked
anti-estrogenic, some anabolic, moderate androgenic, and as a result,
pronounced anti-gonadotropic activities.
Synthetic progesterones are 10-100 times more potent than natural
progesterone, and thus are effective at much lower doses. However,
synthetic progesterones (i.e., progestins) can cause many negative side
effects, such as sudden or partial loss of vision, thrombophlebitis,
pulmonary embolism, cerebral thrombosis, salt and fluid retention,
epilepsy, migraine, asthma, cardiac or renal dysfunction, weight gain,
rise in blood pressure, headaches, depression, decreased glucose tolerance
leading to diabetes in predisposed individuals, acne, alopecia, hirsutism,
decrease in T3 uptake and thyroid regulation.
A disadvantage of conventional patch systems is that many of them either
incorporate drugs in an adhesive or require an adhesive to affix the patch
to patient's skin. These adhesives can irritate the skin, causing patient
non-compliance. Thus, there is a need for a non-adhesive transdermal
delivery system that can deliver therapeutically effective amounts of
hormones such as natural progesterone, progestins, estrogens and
testosterone that will reduce or eliminate the skin irritation experienced
by many patients using current adhesive patch transdermal delivery
systems. This need is satisfied by a particular embodiment of the
invention.
Although patches for the transdermal delivery of estrogen and testosterone
are currently commercially available, progesterone can be obtained
commercially at present only in oral, injectable and suppository forms.
The transdermal delivery of natural progesterone from hydrogel matrix
systems with potential for use in patches has been demonstrated; however,
none of these systems has proven adequate for administration of
therapeutically effective amounts of progesterone. Accordingly, there is a
need in the art for a matrix composition that can transdermally deliver
and maintain therapeutically effective levels of hormones such as natural
progesterone, progestins, estrogens and testosterone in the bloodstream
from a convenient, reliable patch system.
Citation of the references hereinabove shall not be construed as an
admission that such references are prior art to the present invention.
3. SUMMARY OF THE INVENTION
The present invention is directed to compositions for the transdermal
delivery of a hormone selected from the group consisting of progesterone,
progestin, estrogen, and testosterone, or a combination thereof, said
compositions comprising or alternatively consisting or consisting
essentially of: (a) a hydrogel, or a base mixture that when combined with
water forms a hydrogel; (b) a permeation enhancer selected from the group
consisting of urea, hydroxyurea, or an alkylurea; and (c) a hormone
selected from the group consisting of progesterone, progestin, estrogen,
and testosterone, or a combination thereof. In a preferred embodiment, the
hormone is natural progesterone. Natural progesterone is superior to
synthetic forms of progesterone, known as progestins, in treating
gynecological conditions. The invention also provides apparatuses for
transdermal hormone delivery containing the compositions of the invention.
Methods of transdermal drug delivery, and of treatment of disorders
responsive to the administration of hormones, are also provided.
Transdermal delivery according to the invention offers significant
advantages over conventional means of drug administration. It is a
comfortable, convenient and noninvasive means of drug delivery. The
variable rates of absorption and metabolism encountered in oral treatment
are avoided, and side effects such as gastrointestinal irritation and the
like are eliminated. Transdermal drug delivery also makes possible a high
degree of control over blood concentrations of particular drugs.
Transdermal drug delivery according to the invention also helps provide
patients with a drug's maximum therapeutic effect and decreases the risk
of adverse side effects or diminished therapeutic effect due to excessive
or insufficient blood concentrations. The therapeutic effect of a drug is
typically achieved only when the drug is within a specific concentration
range in the bloodstream. This blood concentration range is often called
the drug's "therapeutic window." Below this range the drug may be
ineffective, and above it the drug may cause unwanted side effects. Many
conventional forms of drug delivery administer higher concentrations than
are required in order to maintain effective blood levels between doses.
However, blood levels often fall below effective concentrations prior to
administration of the next dose. Transdermal drug delivery systems using
the compositions of the present invention are designed to maintain a
precise and continuous flow of drug into the bloodstream. This results in
more stable blood concentrations which consistently remain within a drug's
therapeutic window.
In contrast to oral administration, transdermal drug delivery can
frequently maximize a drug's therapeutic effect by avoiding the
gastrointestinal ("GI") tract and "first pass" liver metabolism. Oral drug
delivery is often unreliable because the achievement of therapeutic blood
levels depends on several factors, including the drug's chemical
composition, the patient's physical condition, chemical and physical
reactions between the drug and substances in the GI tract and the timing
of drug administration. Upon GI tract absorption a drug must pass through
the liver before entering the bloodstream. In many instances, the liver
metabolizes a large portion of the drug. As a result, orally dosed drugs
must generally be administered at levels which exceed optimal therapeutic
levels, potentially resulting in adverse side effects.
Transdermal drug delivery systems according to the invention avoid many of
the problems associated with conventional drug delivery, and are capable
of conveniently and consistently delivering drugs over a number of hours
or days. The transdermal drug delivery systems of the invention may also
improve the safety of drug administration, since they can be removed
quickly and easily. If a patient has an adverse reaction to a drug, rapid
removal of the transdermal drug delivery device can minimize the extent of
such an adverse reaction.
The present invention provides compositions comprising (i) a gelling agent
consisting of methylcellulose or at least one natural gum, or a mixture
thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben;
(v) methyl paraben; and (vi) sodium chloride. The compositions of the
present invention may further comprise a glycolic, alcoholic or oil-based
additive such as propylene glycol. The compositions may further comprise
coloring, fragrance or other pharmaceutically acceptable additives. The
compositions of the present invention may also comprise pectin.
In a preferred embodiment, compositions of the present invention consist
essentially of methyl cellulose, a natural gum selected from the xanthan
and guar gums, glucose, propyl paraben, methyl paraben, sodium chloride
and pectin.
Preferably, compositions of the present invention comprise 50-80% (by
weight) methyl cellulose, 15-25% of a natural gum selected from the
xanthan and guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3%
methylparaben, 1-3% sodium chloride and 0.75-3.5% pectin.
Even more preferably, the compositions comprise about 63% methylcellulose,
about 21% guar gum, about 5% glucose, about 3.5% propylparaben, about 3%
methyl paraben, about 3% pectin and about 1.5% sodium chloride.
In one embodiment, the compositions of the present invention further
comprise a drug selected from the group consisting of nicotine,
nitroglycerin, albuterol, VERAPAMIL.RTM., scopolamine, n-butylurea,
fentanyl, morphine, butaconazole, acetylsalicylic acid, MINOXIDIL.RTM.,
lidocaine, racemic menthol, methyl salicylate, benzalkonium chloride,
DEET.RTM., phenobarbitol, iodine, insulin, salicylic acid, nonoxynol-9,
erythromycin, tetracycline, cephalosporins, and acetaminophen.
In a preferred embodiment, the compositions of the present invention
further comprise a substituted urea of the formula R--NH--CO--NH.sub.2
wherein R is hydrogen, hydroxyl, or a lower alkyl having from 1 to 8
carbon atoms selected from the group consisting of methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.
Preferably, the substituted urea is butylurea.
The compositions of the present invention may be provided in the form of a
hydrogel comprising water and a base mixture, said base mixture
comprising: (i) a gelling agent consisting of methylcellulose or at least
one natural gum, or a mixture thereof; (ii) at least one natural gum;
(iii) glucose; (iv) propylparaben; (v) methyl paraben; and (vi) sodium
chloride.
The compositions of the present invention may be provided in the form of a
dry powder comprising
(a) a drug; and
(b) a base mixture comprising (i) a gelling agent consisting of
methylcellulose or at least one natural gum, or a mixture thereof; (ii) at
least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl
paraben; and
(vi) sodium chloride.
The compositions of the present invention may also be provided in the form
of a paste comprising
(a) a drug; and
(b) a base mixture comprising (i) a gelling agent consisting of
methylcellulose or at least one natural gum, or a mixture thereof; (ii) at
least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl
paraben; and (vi) sodium chloride.
The present invention further provides compositions comprising:
(a) a hydrogel comprising water and a base mixture, said base mixture
comprising or consisting essentially of: (i) a gelling agent consisting of
methylcellulose or at least one natural gum, or a mixture thereof; (ii) at
least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl
paraben; and (vi) sodium chloride;
(b) a substituted urea of the formula R--NH--CO--NH.sub.2 wherein R is
hydrogen, hydroxyl or a lower alkyl having from 1 to 8 carbon atoms; and
(c) a hormone selected from the group consisting of progesterone,
progestin, estrogen, and testosterone, or a mixture of any two or more of
the foregoing.
The compositions of the present invention may further comprise a glycolic,
alcoholic or oil-based additive such as propylene glycol. The compositions
may further comprise coloring, fragrance, or other pharmaceutically
acceptable additives. The compositions of the present invention may also
comprise pectin.
Preferably, the hydrogel-forming base mixture of the present invention
consists essentially of methyl cellulose, a natural gum selected from the
xanthan and guar gums, glucose, propyl paraben, methyl paraben, pectin and
sodium chloride.
More preferably, the hydrogel-forming base mixture of the present invention
consists essentially of 50-80% (by weight) methyl cellulose, 15-25% of a
natural gum selected from the xanthan and guar gums, 3-7% glucose, 2-3.5%
propylparaben, 1.5-3% methylparaben, 0.75-3.5% pectin, and 1-3% sodium
chloride. Even more preferably, the base mixture consists essentially of
about 63% methylcellulose, about 21% guar gum, about 5% glucose, about
3.5% propylparaben, about 3% methyl paraben, about 3% pectin and about
1.5% sodium chloride.
Preferably, the compositions of the present invention consist essentially
of:
(a) 3-12% of a base mixture as described above;
(b) 0.5-15% by weight of a substituted urea permeation enhancer of the
formula R--NH--CO--NH.sub.2, wherein R is hydrogen, hydroxyl or lower
alkyl having from 1 to 8 carbon atoms;
(c) 5-20% by weight of a hormone selected from the group consisting of
progesterone, progestin, estrogen, and testosterone, and a mixture of any
two or more of the foregoing;
(d) 0-20% by weight propylene glycol; and
(e) 20-80% water; in which said base mixture and water form a hydrogel.
Even more preferably, the compositions of the present invention consist
essentially of:
(a) about 9% by weight of a base mixture consisting essentially of: about
63% (by weight) methyl cellulose, about 21% guar gum, about 5% glucose,
about 3.5% propylparaben, about 3% methylparaben, about 1.5% sodium
chloride and about 3% pectin;
(b) about 2% by weight of a substituted urea of the formula
R--NH--CO--NH.sub.2, wherein R is hydrogen, hydroxyl or lower alkyl having
from 1 to 8 carbon atoms;
(c) about 10% by weight of progesterone;
(d) about 20% by weight propylene glycol; and
(e) about 59% by weight water; in which said base mixture and water form a
hydrogel.
The compositions of the present invention may be used as vehicles or
carriers for the delivery of a wide variety of drugs to a subject. Drugs
that can be delivered using the compositions of the present invention
include, but are not limited to nicotine, nitroglycerin, albuterol,
VERAPAMIL.RTM., scopolamine, n-butylurea, fentanyl, morphine,
butaconazole, acetylsalicylic acid, MINOXIDIL.RTM., lidocaine, racemic
menthol, methyl salicylate, benzalkonium chloride, DEET.RTM.,
phenobarbitol, iodine, insulin, salicylic acid, nonoxynol-9, erythromycin,
tetracycline, cephalosporins, and acetaminophen.
The compositions of the present invention are particularly useful as
pharmaceutically acceptable bases for the delivery of drugs such as
hormones selected from the group consisting of progesterone, progestin,
estrogen, testosterone, and mixtures of any two or more of the foregoing.
The compositions of the present invention are particularly useful for the
transdermal delivery of these hormones. In a preferred embodiment,
compositions of the present invention are particularly useful for the
transdermal delivery of progesterone.
In another embodiment, the compositions of the present invention are useful
in a variety of vaginal applications. For example, compositions of the
present invention are useful as vaginal lubricants, spermicides, and to
treat vaginal yeast infections.
In specific embodiments, the present invention provides devices for
transdermal delivery of drugs that do not require the use of an adhesive
that has the potential to irritate the skin.
Devices in accordance with the invention may comprise a watch, or are in
the form of a watch. In one embodiment, a watch or watch-like device of
the invention has a watch-case with a recessed chamber on the back face of
the watch-case in contact with the skin. The recessed chamber contains a
wafer having a top face and a bottom face containing a drug and a
pharmaceutically acceptable base. In another embodiment, the recessed
chamber of the watch-case comprises a fluid-filled or hydrogel cushion
later situated against the top face of the drug-containing wafer. In
another embodiment, the recessed chamber of the watch-case comprises a
heating layer having a top face and a bottom face in which the bottom face
of the heating layer is situated against the top face of the
drug-containing wafer. In still another embodiment, the recessed chamber
of the watch-case comprises permanent, closed cell having a top face and a
bottom face, the bottom face of which is situated against the top face of
the heating layer.
In another embodiment, a device for the transdermal delivery of a drug to a
subject is provided which comprises a disc-shaped drug reservoir. The
reservoir has a recessed chamber which can contain a wafer having a top
face and a bottom face comprising a drug and a pharmaceutically acceptable
base. In one embodiment, the reservoir clips on to the back face of a
watch or watch-like device such that drug-containing wafer is maintained
in contact with the subject's skin. In another embodiment, the reservoir
slides onto a band capable of being attache to the limb of a subject such
that the drug-containing wafer is maintained in contact with the skin of
the subject's limb. In another embodiment, the recessed chamber of the
clip-on or slide-on drug reservoir comprises a fluid-filled or hydrogel
cushion later situated against the top face of the drug-containing wafer.
In another embodiment, the recessed chamber of the clip-on or slide-on
drug reservoir comprises a heating layer having a top face and a bottom
face in which the bottom face of the heating layer is situated against the
top face of the drug-containing wafer. In still another embodiment, the
recessed chamber of the clip-on or slide-on drug reservoir comprises
permanent, closed cell having a top face and a bottom face, the bottom
face of which is situated against the top face of the heating layer.
In another embodiment, a device for the transdermal delivery of a drug to a
subject in accordance with the present invention comprises a glove wherein
the inside of the glove is lined with a layer containing a composition of
the invention comprising a pharmaceutically acceptable hydrogel base and a
drug.
In still another embodiment, a device for the trandermal delivery of a drug
to a subject in accordance with the present invention comprises a band or
a strap having a surface coated with a drug-containing composition of the
present invention, wherein the band or strap is capable of being attached
to the limb of a subject such that the drug-containing composition is
maintained in contact with the skin of the subject's limb.
The present invention also provides kits comprising the recessed
chamber-type, the clip-on drug reservoir-type, the slide-on drug
reservoir-type, the glove-type or the band-type of transdermal drug
delivery devices.
The present invention also provides methods for the treatment of conditions
responsive to hormone replacement therapy such as premenstrual syndrome,
menopause, infertility, dysfunctional bleeding, corpus luteum failure,
senile vulvo-vaginitis, hypogonadism and osteoporosis. The invention also
provides methods of contraception in males and females. The invention
further provides a method of delivering a hormone or mixture of hormones
to a subject. These methods of the invention involve placing a composition
of the invention in contact with the skin of a subject such that an
effective amount of the hormone or mixture of hormones is delivered
transdermally to said subject.
The present invention also provides methods for the treatment of vaginal
disorders such as yeast infections. The present invention also provides
methods of providing contraception using spermicides. The present
invention further provides methods for providing vaginal lubrication.
These methods involve placing a composition of the present invention
inside the vagina of a subject.
4. DESCRIPTION OF THE FIGURES
FIG. 1. Cross-sectional view of a Membrane-Moderated Transdermal Drug
Delivery System. The system comprises: a drug reservoir 1 that may contain
a composition of the present invention; a drug-impermeable backing layer
2, which can be plastic, metal, metallic laminate or any other
pharmaceutically acceptable material; a rate-controlling polymeric
membrane 3; and an adhesive layer 4, which can be any adhesive known in
the art. Arrows 5 show an exemplary route of passage of the drug out the
device into the skin. FIG. 1 is adapted from R. Sitruk-Ware, 1989,
"Transdermal Delivery of Steroids," Contraception 39 (1):1-20, at page 9,
FIG. 5.
FIG. 2. Cross-sectional view of an Adhesive Diffusion-Controlled
Transdermal Drug Delivery System. The system comprises: a drug reservoir
layer 1 which may comprise a composition of the present invention; a
drug-impermeable backing layer 2, which can be plastic, metal, metallic
laminate or any other pharmaceutically acceptable material; a
rate-controlling adhesive layer 3; and an adhesive layer 4. The adhesive
layers may comprise any adhesive known in the art. Arrows 5 show an
exemplary route of passage of the drug out the device into the skin. FIG.
2 is adapted from R. Sitruk-Ware, 1989, "Transdermal Delivery of
Steroids," Contraception 39 (1):1-20, at page 10, FIG. 6.
FIG. 3. Cross-sectional view of a Microreservoir-Type Transdermal Drug
Delivery System. The system comprises: an adhesive foam pad 1 made of
flexible polyurethane; an occlusive baseplate 2 comprising an aluminum
foil disc; an adhesive rim 3; microscopic drug reservoirs 4; and a polymer
matrix 5 which may comprise a composition of the present invention. Arrows
6 show an exemplary route of passage of the drug out the device into the
skin. FIG. 3 is adapted from R. Sitruk-Ware, 1989, "Transdermal Delivery
of Steroids," Contraception 39 (1):1-20, at page 12, FIG. 8.
FIG. 4. Cross-sectional view of a Matrix Dispersion-Type Transdermal Drug
Delivery System. The system comprises: a drug-impermeable backing layer 1,
which may be plastic, metal, metallic laminate or any other
pharmaceutically acceptable material; an absorbent pad 2; an occlusive
baseplate 3 comprising an aluminum foil disc; a drug reservoir 4 which may
contain a composition of the present invention; and an adhesive rim 5.
Arrows 6 depict an exemplary route of passage of the drug out the device
into the skin. FIG. 4 is adapted from R. Sitruk-Ware, 1989, "Transdermal
Delivery of Steroids," Contraception 39 (1):1-20, at page 11, FIG. 7.
FIG. 5. Perspective view of the top face of a recessed-chamber type of
transdermal drug delivery device of the present invention, comprising: a
watch case 1 and a band or strap 2.
FIG. 6. Perspective view of the back face of one embodiment of the
recessed-chamber type of transdermal drug delivery device of the present
invention, comprising: a watch case 1; a recessed chamber 2 capable of
containing a wafer comprising a drug and a pharmaceutically acceptable
base, which may comprise a composition of the present invention; and a
band or strap 3.
FIG. 7. Cross-sectional view of one embodiment of the recessed-chamber type
of transdermal drug delivery device of the present invention, comprising:
a watch case 1; a recessed chamber 2; a band or strap 3; and a wafer 4
comprising a drug and a pharmaceutically acceptable base which may
comprise a composition of the present invention.
FIG. 8. Cross-sectional view of another embodiment of the recessed-chamber
type of transdermal drug delivery device of the present invention,
comprising: a watch case 1; a recessed chamber 2; a band or strap 3; a
fluid-filled cushion 4; a wafer 5 comprising a drug and a pharmaceutically
acceptable base which may comprise a composition of the present invention;
and a non-slip material 6 on the rim of the recessed chamber.
FIG. 9. Perspective view of one embodiment of the top face of a watch or
watch-like device having the clip-on drug reservoir type of transdermal
drug delivery device of the present invention attached to its back face
comprising: a watch case 1; a band or strap 2; and a clip-on drug
reservoir 3.
FIG. 10. Cross-sectional view of one embodiment of the clip-on or slide-on
drug reservoir type of transdermal drug delivery device of the present
invention, comprising: a plurality of clips 1 capable of attaching the
clip-on drug reservoir to the back face of a watch or watch-like device; a
recessed chamber 2; a wafer 3 comprising a drug and a pharmaceutically
acceptable base which may comprise a composition of the present invention;
and a soft flair skin seal 4.
FIG. 11. Cross-sectional view of another embodiment of the clip-on or
slide-on drug reservoir type of transdermal drug delivery device of the
present invention, comprising: a plurality of clips 1 capable of attaching
the drug reservoir to the back face of a watch or watch-like device; a
recessed chamber 2; a permanent closed cell 3 comprising dense
polyethylene capable of providing slight downward pressure on the
drug-containing wafer; a heating layer 4 comprising a means for heating
the drug-containing wafer; a wafer 5 comprising a drug and a
pharmaceutically acceptable base which may comprise a composition of the
present invention; and a soft flair skin seal 6.
FIG. 12. Perspective view of the bottom face of one embodiment of the
clip-on or slide-on drug reservoir type of transdermal drug delivery
device of the present invention, comprising: a plurality of clips 1
capable of attaching the clip-on drug reservoir to the back face of a
watch or watch-like device; a recessed chamber 2; a soft flair skin seal
3; and a plurality of slots 4 that are capable of having a band or strap
threaded through them.
FIG. 13. Cross-sectional view of a watch having one embodiment of the
clip-on drug reservoir type of transdermal drug delivery device of the
present invention attached to its back face, comprising: a watch case 1; a
band or strap 2; a clip-on drug reservoir 3; a recessed chamber 4; a wafer
5 comprising a drug and a pharmaceutically acceptable base which may
comprise a composition of the present invention; and a soft flair skin
seal 6.
FIG. 14. Cross-sectional view of one embodiment of the slide-on drug
reservoir type of transdermal drug delivery device of the present
invention attached to a band, comprising: a slide-on drug reservoir 1; a
band or strap 2; a recessed chamber 3; a wafer 4 comprising a drug and a
pharmaceutically acceptable base which may comprise a composition of the
present invention; and a soft flair skin seal 5.
FIG. 15. Perspective view of the bottom face of one embodiment of the
slide-on drug reservoir type of transdermal drug delivery device of the
present invention, comprising: a plurality of slots 1 that are capable of
having a band or strap threaded through them; a wafer 2 comprising a drug
and a pharmaceutically acceptable base which may comprise a composition of
the present invention; a soft flair skin seal 3; and a band or strap 4.
FIG. 16. Cross-sectional view of the Single-Chamber Diffusion Cell used in
the skin permeation measurements described in the Examples of the present
invention. The cell comprises: a retaining nut 1; a flanged PVC washer 2
with aluminum foil coating 3; an o-ring 4; a skin disc 5, which is
cemented to a nylon washer 6; a teflon-coated magnetic stirring button 7;
receptor fluid 8; and a stopper 9 comprising a foil-coated flanged washer.
FIG. 17. A graph depicting the cumulative amount of progesterone
penetrated, (.mu.g/cm.sup.2, y-axis) against time, (hours x-axis), from
sample A-1 through a dialysis membrane, as described in Section 6.2.2. The
graph shows a penetration rate of 30.8 .mu.g/cm.sup.2 of progesterone
through the dialysis membrane.
FIG. 18. A graph depicting the cumulative amount of progesterone
penetrated, (.mu.g/cm.sup.2, y-axis) against time, (hours, x-axis), from
covered and not-covered samples of A-1 through human skin, as described in
Section 6.2.3. Curve 1 corresponds to the covered sample of A-1 and Curve
2 corresponds to the not-covered sample of A-1.
FIG. 19. A graph depicting the cumulative amount of progesterone
penetrated, (.mu.g/cm.sup.2, y-axis) against time, (hours, x-axis), from
samples A-1, A-2, and A-3 through human skin, as described in Section
6.2.4. Curve 1, corresponding to sample A-1, shows a rate of 3.1
.mu.g/cm.sup.2 /hr. Curve 2, corresponding to sample A-2, shows a rate of
1.9 .mu.g/cm.sup.2 /hr. Curve 3, corresponding to sample A-3, shows a rate
of 9.8 .mu.g/cm.sup.2 /hr.
5. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compositions comprising (i) a gelling agent
consisting of methylcellulose or at least one natural gum, or a mixture
thereof; (ii) at least one natural gum; (iii) glucose; (iv) propylparaben;
(v) methyl paraben; and (vi) sodium chloride.
The compositions of the present invention may further comprise a glycolic,
alcoholic or oil-based additive. Examples of the glycolic, alcoholic, or
oil-based additives that may be used in the compositions of the present
invention include, but are not limited to propylene glycol, glycerin,
mineral oil, corn oil, bran oil, rice oil, soy oil, ethylene glycol,
xylene and alcohols such as ethyl alcohol. A preferred additive is
propylene glycol. The compositions may further comprise coloring,
fragrance or other pharmaceutically acceptable additives. The compositions
of the present invention may also comprise pectin.
In a preferred embodiment, compositions of the present invention consist
essentially of methyl cellulose, a natural gum selected from the xanthan
and guar gunms, glucose, propyl paraben, methyl paraben, sodium chloride
and pectin.
Preferably, compositions of the present invention comprise 50-80% (by
weight) methyl cellulose, 15-25% of a natural gum selected from the
xanthan and guar gums, 3-7% glucose, 2-3.5% propylparaben, 1.5-3%
methylparaben, 1-3% sodium chloride and 0.75-3.5% pectin. Even more
preferably, the compositions comprise about 63% methylcellulose, about 21%
guar gum, about 5% glucose, about 3.5% propylparaben, about 3% methyl
paraben, about 3% pectin and about 1.5% sodium chloride.
In specific embodiments, drugs are included in the compositions of the
present invention.
In a preferred embodiment, the compositions of the present invention
further comprise a substituted urea of the formula R--NH--CO--NH.sub.2
wherein R is hydrogen, hydroxyl, or a lower alkyl having from 1 to 8
carbon atoms selected from the group consisting of methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl and octyl.
Preferably, the substituted urea is butylurea.
The compositions of the present invention may be provided in the form of a
dry powder comprising
(a) a drug; and
(b) a base mixture comprising (i) a gelling agent consisting of
methylcellulose or at least one natural gum, or a mixture thereof; (ii) at
least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl
paraben; and
(vi) sodium chloride.
The compositions of the present invention may also be provided in the form
of a paste comprising
(a) a drug; and
(b) a base mixture comprising (i) a gelling agent consisting of
methylcellulose or at least one natural gum, or a mixture thereof; (ii) at
least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl
paraben; and
(vi) sodium chloride.
Dry powder and paste compositions of the present invention can form
hydrogels upon the addition of water.
The present invention provides compostions for the transdermal delivery or
hormones such as progesterone, progestin, estrogen, testosterone, or
combinations thereof, said compositions alternatively consisting of or
consisting essentially of: (a) a hydrogel, or a base mixture that when
combined with water forms a hydrogel; (b) a permeation enhancer selected
from the group consisting of urea, hydroxyurea, or an alkylurea; and (c) a
hormone selected from the group consisting of progesterone, progestin,
estrogen, testosterone, or combinations thereof. In preferred embodiment,
the hormone is natural progesterone. Natural progesterone is superior to
synthetic forms of progesterone, known as progestins, in treating
gynecological conditions.
The invention also provides apparatuses for transdermal hormone delivery
containing the compositions of the invention. Methods of transdermal
delivery, and of treatment of disorders responsive to the administration
of hormones are also provided. The compositions of the invention provide
more effective and efficient means for delivery of a therapeutically
effective amount of the hormone(s) contained therein to the bloodstream of
a patient.
The present invention further provides compositions comprising:
(a) a hydrogel comprising water and a base mixture, said base mixture
comprising or consisting essentially of: (i) a gelling agent consisting of
methylcellulose or at least one natural gum, or a mixture thereof; (ii) at
least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl
paraben; and (vi) sodium chloride;
(b) a substituted urea of the formula R--NH--CO--NH.sub.2 wherein R is
hydrogen, hydroxyl or a lower alkyl having from 1 to 8 carbon atoms; and
(c) a hormone selected from the group consisting of progesterone,
progestin, estrogen, and testosterone, or a mixture of any two or more of
the foregoing.
The composition may also optionally contain a glycolic, alcoholic or
oil-based additive. Examples of the glycolic, alcoholic or oil-based
additivies that may be used in the compositions of the present invention
include propylene glycol, glycerin, mineral oil, corn oil, bran oil, rice
oil, soy oil, ethylene glycol, xylene, and alcohols such as ethyl alcohol.
A preferred additive is propylene glycol. The compositions may also
contain colorings, fragrances or other pharmaceutically acceptable
additives. Preferably, the water used in the inventive compositions is
distilled water. The compositions of the present invention may also
comprise pectin.
Preferably, the hydrogel-forming base mixture of the present invention
consists essentially of methyl cellulose, a natural gum selected from the
xanthan and guar gums, glucose, propyl paraben, methyl paraben, pectin and
sodium chloride.
More preferably, the hydrogel-forming base mixture of the present invention
consists essentially of 50-80% (by weight) methyl cellulose, 15-25% of a
natural gum selected from the xanthan and guar gums, 3-7% glucose, 2-3.5%
propylparaben, 1.5-3% methylparaben, 0.75-3.5% pectin, and 1-3% sodium
chloride. Even more preferably, the base mixture consists essentially of
about 63% methylcellulose, about 21% guar gum, about 5% glucose, about
3.5% propylparaben, about 3% methyl paraben, about 3% pectin and about
1.5% sodium chloride.
Preferably, the compositions of the present invention consist essentially
of:
(a) 3-12% of a base mixture as described above;
(b) 0.5-15% by weight of a substituted urea permeation enhancer of the
formula R--NH--CO--NH.sub.2, wherein R is hydrogen, hydroxyl or lower
alkyl having from 1 to 8 carbon atoms;
(c) 5-20% by weight of a hormone selected from the group consisting of
progesterone, progestin, estrogen, and testosterone, and a mixture of any
two or more of the foregoing;
(d) 0-20% by weight propylene glycol; and
(e) 20-80% water; in which said base mixture and water form a hydrogel.
Even more preferably, the compositions of the present invention consist
essentially of:
(a) about 9% by weight of a base mixture consisting essentially of: about
63% (by weight) methyl cellulose, about 21% guar gum, about 5% glucose,
about 3.5% propylparaben, about 3% methylparaben, about 1.5% sodium
chloride and about 3% pectin;
(b) about 2% by weight of a substituted urea of the formula
R--NH--CO--NH.sub.2, wherein R is hydrogen, hydroxyl or lower alkyl having
from 1 to 8 carbon atoms;
(c) about 10% by weight of progesterone;
(d) about 20% by weight propylene glycol; and
(e) about 59% by weight water; in which said base mixture and water form a
hydrogel.
4.1 HYDROGEL BASE MIXTURE
The hydrogel-forming base mixture may optionally include pectin.
Natural gums which may be used in the hydrogel-forming base mixture include
guar gum and xanthin gum. The hydrogel-forming base mixture preferably
comprises a methylcellulose gelling agent; however inclusion of
methylcellulose is not required. In place of the methylcellulose gelling
agent, additional amounts of natural gums such as guar or xanthin gums, or
mixtures thereof, may be substituted.
The hydrogel-forming base mixture of the present invention is preferably
made by way of example as follows: A dry powder form is mixed together of
each of the natural gum, glucose, propylparaben, methylparaben, and sodium
chloride ingredients. Methyl cellulose and pectin dry powders are
optionally included. The dry powder mixture is then micronized to a size
of approximately one micron. Upon the addition of water, the mixture forms
a hydrogel, which varies from a semi-fluid to a solid rubber consistency,
depending on the amount of water added.
Preferably, the hydrogel-forming base mixture of the present invention
consists essentially of 50-80% (percentages are by weight) methyl
cellulose, 15-25% of a natural gum, 3-7% glucose, 2-3.5% propylparaben,
1.5-3% methylparaben, and 1-3% sodium chloride. Optionally, the mixture
may include 0.75-3.5% pectin. Even more preferably, the base mixture
consists essentially of 63% methylcellulose, 21% guar gum, 5% glucose,
3.5% propylparaben, 3% methyl paraben, 3% pectin and 1.5% sodium chloride.
All seven of these ingredients that may be used in the base mixture of the
present invention are well known materials which are readily available
from a wide variety of commercial sources such as the Aldrich Chemical Co.
(Milwaukee, Wis.), or the Sigma Chemical Co. (St. Louis, Mo.), etc.
In preferred embodiment, the present invention provides a composition for
the transdermal delivery of natural progesterone comprising, or
alternatively, consisting essentially of:
(a) 3-12% of a base mixture comprising: (i) a gelling agent consisting of
methylcellulose or at least one natural gum, or mixtures thereof; (ii) at
least one natural gum; (iii) glucose; (iv) propylparaben; (v) methyl
paraben; and (vi) sodium chloride; which may optionally include pectin;
(b) 0.5-15% by weight of a substituted urea permeation enhancer of the
formula R--NH--CO--NH.sub.2, wherein R is hydrogen, hydroxyl or lower
alkyl having from 1 to 8 carbon atoms;
(c) 5-20% by weight of a hormone selected from the group consisting of
progesterone, progestins, estrogens, and testosterone, or mixtures
thereof;
(d) 0-20% by weight propylene glycol; and
(e) 20-80% water; in which said base mixture and water combine to form a
hydrogel.
A particularly preferred embodiment of the present invention is directed to
a composition for the transdermal delivery of natural progesterone
consisting of:
(a) 9% by weight of a base mixture consisting essentially of (1)
methylcellulose; (2) guar gum; (3) glucose; (4) propylparaben; (5) methyl
paraben; (6) pectin; and (7) sodium chloride;
(b) 2% by weight of a substituted urea permeation enhancer of the formula
R--NH--CO--NH.sub.2, wherein R is hydrogen, hydroxyl or lower alkyl having
from 1 to 8 carbon atoms;
(c) 10% by weight of natural progesterone;
(d) 20% by weight propylene glycol; and
(e) 59% by weight water; in which said base mixture and water form a
hydrogel.
In a preferred embodiment, the above composition of the present invention
is formed by first mixing the base mixture powder, substituted alkyl urea
and progesterone in propylene glycol to form a paste. The paste is then
heated without boiling until the progesterone and substituted alkyl urea
are dissolved and the paste becomes a liquid. This hot glycol mixture is
then added to tepid water while stirring with a blade type stirring unit
at a speed sufficient to from a vortex at the surface. The hot glycol
mixture is added to the stirring water in this manner for 5 to 15 minutes,
or until the proper or desired viscosity is achieved. The mixture is then
removed from the stirred container and placed in a barrier container for
storage to prevent evaporation. Shelf life of the finished product should
be several years.
4.2 UREA AND UREA DERIVATIVES
The compositions enhancers of the present invention can comprise
monosubstituted lower-alkyl ureas of the formula:
R--NH--CO--NH.sub.2
wherein R is hydrogen, hydroxyl or lower alkyl having from 1 to 8 carbon
atoms. Preferably, the lower alkyl group has from 1 to 6 carbon atoms;
more preferably from 1 to 4 carbon atoms; and most preferably from 3 to 4
carbon atoms. Specific examples of the lower alkyl group R include methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl,
heptyl and octyl. A particularly preferred monosubstituted lower-alkyl
urea useful in the present invention is butylurea. The monosubstituted
lower alkyl ureas are known compounds and are readily available from
commercial sources such as the Aldrich Chemical Co. (Milwaukee, Wis.). In
a preferred embodiment, the permeation enhancer is butylurea. When the
compositions of the present invention comprising urea derivatives are used
for the transdermal delivery of drugs, the urea derivatives may function
as transdermal penetration enhancers. Urea derivatives such as butylurea
can also function as spermicides when the compositions of the present
invention are used in vaginal applications.
4.3 DRUGS
Drugs which may be used in the compositions of the present invention and
the disorders which such compositions may be used to treat include, but
are not limited to nicotine for smoking cessation, nitroglycerin for
angina pectoris, albuterol as an antiasthmatic, VERAPAMIL.RTM. for
hypertension, scopolamine for motion sickness, n-butylurea for herpes
sores, fentanyl for acute pain, morphine for pain, steroid hormones for
osteoporosis, estrogen and progestin for hormonal replacement,
butaconazole for vaginal yeast infection, acetylsalicylic acid as aspirin
for pain, MINOXIDIL.RTM. for hair growth, lidocaine for pain, racemic
menthol for pain, methyl salicylate for pain, benzalkonium chloride as a
germicide, DEET.RTM. for insect control, phenobarbitol as a sedative,
iodine as an antiseptic, insulin as an antidiabetic, salicylic acid as a
topical keratolytic, nonoxynol-9 as a spermicide, erythromycin as an
antibiotic, tetracycline as an antibiotic, cephalosporins as an antibotic,
and acetaminophen for pain. In a specific embodiment, the drug has utility
in the treatment of a human disease or animal disorder. The present
invention also provides methods for treating the above-listed disorders.
Examples of hormones that may be delivered to a subject using the
compositions of the present invention include progesterone, progestin,
estrogen and testosterone, or a mixture of any two or more of the
foregoing. Depending on the application, the present invention may be used
to deliver each of these hormones alone, or in various combinations. In a
preferred emodiment, the hormones are delivered transdermally using the
compositions of the present invention. Specific examples of progestins
useful in the present invention include but are not limited to are medroxy
progesterone acetate, norethindrone, norethindrone acetate, norgestrel,
and ethynodiol diacetate. Specific examples of estrogens useful in the
present invention include but are not limited to 17-.beta.-estradiol,
diethylstilbestrol, estropipate (formerly known as piperazine estrone
sulfate), estrone and estriol.
A most preferred hormone is pregn-4-ene-3,20-dione, which has a molecular
weight of 314.47, and is also known as "natural progesterone", or simply,
"progesterone." Natural progesterone is produced in the human body, but it
can be also be isolated from certain plants, and is available
commercially. For example, micronized powder forms of natural progesterone
useful in the present invention are available from both the Upjohn
Chemical Co. (Kalamazoo, Mich.) and the Berlex Chemical Co. (North
Surburban, Ill.).
As discussed above, the compositions of the present invention are also
suitable for delivery, transdermal and otherwise, of synthetic progestins,
estrogens such as 17-.beta.-estradiol and testosterone. Synthetic
progestins, estrogens and testosterone which may be used in the present
invention are readily available from a variety of commercial sources well
known to those skilled in the art.
4.4 TRANSDERMAL DELIVERY DEVICES
The means for administration of the compositions of the present invention
to a patient may vary. In one embodiment, compositions of the present
invention are administered vaginally. In another embodiment, the
compositions are delivered transdermally, which but necessarily involves
application of the composition to a selected intact surface of the skin
for a period of time sufficient to provide the desired blood level of the
drug. Preferably, the composition is administered to a patient via use of
a transdermal delivery device. Various transdermal systems are known and
may be used to administer therapeutically effective amounts of hormones
using the compositions of the invention. Four general types of transdermal
drug delivery devices are taught, for example, by R. Sitruk-Ware (1989,
"Transdermal Delivery of Steroids," Contraception 39 (1):1-20. Transdermal
delivery devices are also disclosed by Pfister and Hsieh (1990,
"Permeation Enhancers Compatible with Transdermal Drug Delivery Systems:
Part II: System Design Considerations," Pharmaceutical Technology (October
1990): 55-60.
For example, the composition of the present invention may be administered
using a membrane-moderated transdermal drug delivery system, as shown in
FIG. 1. In this type of system, the inventive composition is contained
within the drug reservoir 1. The rate of delivery of the hormone through
the skin is simultaneously enhanced by use of the hydrogel and the
monosubstituted alkyl urea penetration enhancer of the invention and
moderated by a rate-controlling polymeric membrane 3. The inventive
composition may also be administered to a patient via an adhesive
diffusion-controlled transdermal drug delivery system, (see FIG. 2) in
which the rate of delivery of the hormone through the skin is
simultaneously enhanced by use of the hydrogel and the monosubstituted
alkyl urea penetration enhancer of the invention and moderated by a
rate-controlling adhesive layer 3.
Another type of transdermal drug delivery device suitable for use with the
present invention is the microreservoir-type system (see FIG. 3). As
applied to the present invention, this type of system consists of a
suspension of the solid hormone in the inventive hydrogel-forming base
mixture. The hormone suspension is dispersed homogeneously in a lipophilic
polymer to form numerous microscopic spheres of drug reservoir 4. This
dispersion is thermodynamically unstable and is stabilized by
cross-linking the polymer chains in situ. The mixture is formed into a
disc and is then covered by an occlusive baseplate 2 and optionally
surrounded by an adhesive rim 3.
A preferred transdermal delivery device useful for application of the
compositions of the present invention is a matrix dispersion type system
(FIG. 4). For use in this type of system, the composition of the present
invention is molded into a disc of a certain thickness and is applied onto
an occlusive baseplate 3 in a compartment fabricated from a
drug-impermeable plastic backing 1. An adhesive may be applied along the
circumference of the device to form an adhesive rim 5 around the disc.
Generally, adhesives used in transdermal delivery devices have the
potential to cause skin irritation. Accordingly, in specific embodiments,
the present invention provides transdermal delivery devices in form of a
watch or watch-like device which have the advantage that an adhesive is
not necessary to maintain contact of a drug-containing transdermal
delivery composition with the patient's skin.
In one embodiment, a watch or watch-like device of the invention has a
watch-case with a recessed chamber on the back face of the watch-case in
contact with the skin. The recessed chamber contains a wafer having a top
face and a bottom face containing a drug and a pharmaceutically acceptable
base. In another embodiment, the recessed chamber of the watch-case
comprises a fluid-filled or hydrogel cushion later situated against the
top face of the drug-containing wafer. In another embodiment, the recessed
chamber of the watch-case comprises a heating layer having a top face and
a bottom face in which the bottom face of the heating layer is situated
against the top face of the drug-containing wafer. In still another
embodiment, the recessed chamber of the watch-case comprises permanent,
closed cell having a top face and a bottom face, the bottom face of which
is situated against the top face of the heating layer.
The heating layer of the inventive devices can comprise a printed circuit
board or a plastic or metallic layer which contains a plurality of metal
electrical wires or lines comprising circuitry which provide heating. The
heating layer of the inventive devices can be battery-powered or
solar-powered. In one embodiment the heating layer is powered via the
battery of the watch. In another embodiment, the heating layer is powered
by a solar cell.
The permanent, closed cell layer of the inventive devices can comprise a
dense polymeric material. The permanent closed cell layer provides sight
downward pressure on the drug filled wafer, to aid in maintaining contact
of the wafer with the subject's skin.
In another embodiment, a device for the transdermal delivery of a drug to a
subject is provided which comprises a disc-shaped drug reservoir. The
reservoir has a recessed chamber which can contain a wafer having a top
face and a bottom face comprising a drug and a pharmaceutically acceptable
base. The drug reservoir may comprise clear plastic or vinyl.
In one embodiment, the reservoir clips on to the back face of a watch or
watch-like device such that drug-containing wafer is maintained in contact
with the subject's skin. In a specific embodiment, the reservoir clips
over the posts and band of the wafer. In another embodiment, the reservoir
slides onto a band capable of being attached to the limb of a subject such
that the drug-containing wafer is maintained in contact with the skin of
the subject's limb. In another embodiment, the recessed chamber of the
clip-on or slide-on drug reservoir comprises a fluid-filled or hydrogel
cushion later situated against the top face of the drug-containing wafer.
In another embodiment, the recessed chamber of the clip-on or slide-on
drug reservoir comprises a heating layer as described above having a top
face and a bottom face in which the bottom face of the heating layer is
situated against the top face of the drug-containing wafer. In still
another embodiment, the recessed chamber of the clip-on or slide-on drug
reservoir comprises permanent, closed cell as described above having a top
face and a bottom face, the bottom face of which is situated against the
top face of the heating layer.
In another embodiment, a device for the transdermal delivery of a drug to a
subject in accordance with the present invention comprises a glove wherein
the inside of the glove is lined with a layer containing a composition of
the invention comprising a pharmaceutically acceptable hydrogel base and a
drug.
In still another embodiment, a device for the trandermal delivery of a drug
to a subject in accordance with the present invention comprises a band or
a strap having a surface coated with a drug-containing composition of the
present invention, wherein the band or strap is capable of being attached
to the limb of a subject such that the drug-containing composition is
maintained in contact with the skin of the subject's limb.
The present invention also provides kits comprising the recessed
chamber-type, the clip-on drug reservoir-type, the slide-on drug
reservoir-type, the glove-type or the band-type of transdermal drug
delivery devices.
In the case of the recessed-chamber water type of transdermal drug delivery
device, the kit may comprise a watch or watch-like device with a recessed
chamber and comprising a band or strap, and a plurality of drug-containing
wafers. The wafers may be provided in sealed packages for long shelf life.
In the case of the clip-on or slide-on type of transdermal drug delivery
device, the kit may comprise at least one drug reservoir, which may be
clear plastic, vinyl or some other acceptable material, and a plurality of
drug-containing wafers. Again, the wafers may be provided in sealed
packages for long shelf life.
One embodiment of the watch-like device of the present invention provides a
recessed-chamber type of transdermal drug delivery device. A perspective
view of the front face of this device is shown in FIG. 5. The device
comprises a watch case (1) and a band or strap (2) to attach the device to
a limb (e.g., wrist, arm or leg) of the user. The back face (FIG. 6) of
the device has a recessed-chamber capable (2) of containing a
drug-containing wafer, which may comprise a composition of the present
invention. In a specific embodiment, the recessed chamber of the watch is
approximately 3.6 cm in diameter, corresponding to an area of about 10
cm.sup.2. The chamber is at least deep enough to accommodate a
drug-containing wafer approximately 1.5 mm thick. When the wafer loses its
ability to deliver the drug, the patient can simply replace it with
another "refill" wafer.
The watch case may comprise stainless steel or plastic, and the recessed
chamber may be lined with teflon or some other inert material. Optionally,
the rim of the recessed chamber is coated with a non-slip or a soft flair
skin seal material to aid in maintaining contact of the drug-containing
wafer with the user's skin, and to prevent the drug-containing wafer from
drying out. The front face of the watch need not actually contain a
functional watch dial, although such can be the case.
Another embodiment of the recessed-chamber type of transdermal drug
delivery device, shown in FIG. 8, comprises a recessed chamber 2 deep
enough to contain both a drug-containing wafer 2 and a fluid-filled
cushion 4. The fluid-filled cushion may comprise the hydrogel alone,
without the hormone. In a specific embodiment, the recessed chamber is
deep enough to accommodate both a 1.5 mm thick hormone-containing wafer
and a fluid-filled cushion on the roof of the chamber. This fluid cushion
prevents the wafer from buckling and minimizes air bubbles. The device of
this embodiment may also comprise a soft, non-slip material 6 on the rim
of the recessed chamber.
Another embodiment of the watch-like device of the present invention
provides a clip-on drug reservoir type of transdermal drug delivery
device. A perspective view of the top face of the clip-on drug reservoir
type transdermal drug delivery device of the present invention is shown in
FIG. 9, comprising a watch case 1, a band or strap 2 and a clip-on drug
reservoir 3. The clip-on drug reservoir transdermal drug delivery device
of the present invention (FIG. 10) comprises a plurality of clips 1
capable of attaching the clip-on drug reservoir to the back face of a
watch; a recessed chamber 2; a drug-containing wafer 3 which may comprise
a composition of the present invention; and a soft flair skin seal 4. The
front face of the watch need not actually contain a functional watch dial,
although such can be the case.
FIG. 13 shows a cross-sectional view of a watch having the clip-on drug
reservoir type of transdermal drug delivery device of the present
invention attached to its back face, comprising: a watch case 1; a band or
strap 2; the clip-on drug reservoir 3 of the present invention; a recessed
chamber 4, a drug-containing wafer 5; and a soft flair skin seal 6.
Another preferred embodiment of the present invention which also eliminates
the need for an adhesive is a glove lined with the hormone-containing
composition of the present invention. The glove may be latex or any
material that is compatible with the compositions of the present
invention. This embodiment of the invention is suitable when 24 hour
contact of patient's skin with the hormone-containing composition of the
invention is not necessary to achieve therapeutically effective blood
levels of the hormone. The patient simply wears the lined gloves to bed
and then removes them in the morning and washes their hands.
In another preferred embodiment of the invention, a means is provided for
heating the hormone-containing composition while it is in contact with the
patient's skin. Such heating increases the rate of penetration of the drug
into the patient's bloodstream. For example, a battery-powered heater
capable of warming the system approximately 10.degree. F. above ambient
temperature can be built into the watch-like transdermal device of the
present invention to increase the delivery rate of the hormone through the
patient's skin.
In preferred embodiments, use of the compositions of the invention does not
involve topical pre-administration of acetone or similar solvents in order
to achieve transdermal delivery of therapeutically effective amounts to
the bloodstream.
4.5 THERAPEUTIC USES
As discussed above, the compositions of the present invention may contain a
wide variety of drugs, and may be used to treat a wide variety of
disorders. In a preferred embodiments, the present invention provides
methods for treatment of disorders responsive to the administration of
hormones comprising administering to the patient transdermally a
composition of the invention comprising a therapeutically effective amount
of a hormone selected from the group consisting of progesterone,
progestin, estrogen, and testosterone, and a mixture of any two or more of
the foregoing.
The compositions of the present invention are useful for treating a variety
of disorders which benefit from hormone replacement therapy, including
premenstrual syndrome, menopausal symptoms, infertility, and osteoporosis.
A variety of gynecological problems in women such as dysfunctional
bleeding, corpus luteum failure, and post-menopausal senile
vulvo-vaginitis may also be treated with the compositions of the present
invention, as well as male disorders such as hypogonadism. The
compositions of the present invention may also be used to provide
contraception to male and female subjects.
The subject is preferably an animal, including but not limited to animals
such as cows, pigs, chickens, etc., and is preferably a mammal, and most
preferably human. Human subjects may be male or female. Obviously, when
the condition being treated is one specific to women, such as premenstrual
syndrome, menopausal symptoms, and gynecological problems, the subject is
a woman.
The present invention provides compositions useful for providing
contraception to female subjects comprising progesterone, progestins,
estrogens and mixtures thereof. Specifically, compositions of the present
invention comprising progesterone, mixtures of progesterone and one or
more estrogens, or mixtures of one or more estrogens and one or more
progestins may be used to provide contraception to females. Compositions
of the present invention comprising testosterone are useful for providing
contraception to male subjects.
Compositions of the present invention comprising estrogen are particularly
useful in treatment of menopause. At the onset of menopause, women lose
their ability to produce estrogen. A diminished estrogen supply in
post-menopausal women can cause such symptoms as hot flashes, insomnia,
vaginal atrophy, irritability, anxiety, moodiness and excessive sweating.
Natural or synthetic estrogens may be formulated into the compositions of
the present invention for the treatment of these menopausal symptoms.
Estrogen alone may be used to treat menopause in some women. However,
women who use estrogen and who have an intact uterus preferably also take
progesterone to prevent uterine cancer.
Compositions of the present invention comprising estrogen, progesterone or
mixtures thereof may be used to treat or prevent osteoporosis. Estrogen is
known to prevent bone loss, while progesterone is known to stimulate bone
growth. Osteoporosis is a progressive deterioration of the skeletal system
through the loss of bone mass, and is related to the inability to produce
estrogen. According to the National Osteoporosis Foundation, osteoporosis
currently affects approximately 25 million people in the United States. It
is estimated that 80% of all hip fractures in elderly patients are
associated with osteoporosis.
Corpus luteum failure is another condition that the compositions of the
present invention may be used to treat, and can result in infertility
and/or irregular bleeding.
Compositions of the present invention comprising low dosages of
testosterone can be used to treat senile vulvo-vaginitis, a
post-menopausal condition.
Compositions of the present invention comprising natural progesterone,
synthetic progestins, estrogens and mixtures thereof may be used to
provide contraception to a subject.
Accordingly, the present invention provides methods for the treatment of
premenstrual syndrome, menopausal symptoms, infertility, osteoporosis,
dysfunctional bleeding, corpus luteum failure, post-menopausal senile
vulvo-vaginitis and hypogonadism, and methods for providing contraception,
by using compositions of the present invention containing one or more
hormones. The methods entail providing a composition of the present
invention comprising a hydrogel-forming base mixture, a skin permeation
enhancer, a hormone selected from the group consisting of natural
progesterone, progestins, estrogens, testosterone and mixtures thereof, an
optional glycolic, alcoholic or oil-based additive, and water, and
contacting said composition to the skin of a patient to permit the hormone
in the composition to be absorbed into the skin.
In one embodiment, the present invention provides a method for the
treatment of premenstrual syndrome in which a composition of the present
invention comprising natural progesterone is contacted with the skin of a
patient suffering from premenstrual syndrome. In another embodiment, the
present invention provides a method for the treatment of menopausal
symptoms such as hot flashes, insomnia, vaginal atrophy, irritability,
anxiety, moodiness and excessive sweating in which a composition of the
present invention comprising a hormone selected from the group consisting
of natural progesterone, progestins, estrogens, testosterone, and mixtures
thereof, is contacted with the skin of a patient suffering from any of
such symptoms. In another embodiment, the present invention provides a
method for the treatment of infertility in which a composition of the
present invention comprising natural progesterone is contacted with the
skin of a patient suffering from any of such symptoms.
In still another embodiment, the present invention provides a method for
the treatment of osteoporosis in which a composition of the present
invention comprising natural progesterone, estrogen, or a mixture thereof
is contacted with the skin of a patient suffering from osteoporosis. In
still another embodiment, the present invention provides a method for the
prevention of osteoporosis in which a composition of the present invention
comprising natural progesterone, estrogen, or a mixture thereof is
contacted with the skin of a patient who has the potential to develop
osteoporosis.
In another embodiment, the present invention provides a method for the
treatment of dysfunctional bleeding in which a composition of the present
invention comprising natural progesterone or a mixture of natural
progesterone and an estrogen is contacted with the skin of a patient
suffering from dysfunctional bleeding. In another embodiment, the present
invention provides a method for the treatment of corpus luteum failure in
which a composition of the present invention comprising natural
progesterone or a mixture of natural progesterone and an estrogen is
contacted with the skin of a patient suffering from corpus luteum failure.
In another embodiment, the present invention provides a method for the
treatment of post-menopausal senile vulvo-vaginitis in which a composition
of the present invention comprising testosterone is contacted with the
skin of a patient suffering from senile vulvo-vaginitis.
In another embodiment, the present invention provides a method for the
treatment of hypogonadism in which a composition of the present invention
comprising testosterone is contacted with the skin of a patient suffering
from hypogonadism.
In another embodiment, the present invention provides a method for
providing contraception in which a composition of the present invention
comprising natural progesterone, synthetic progestins, estrogens or
mixtures thereof is contacted with the skin of a subject in need of
contraception. The compositions of the invention may be sued to provide
contraception to both males and females.
In the methods of this invention, the inventive composition comprising the
appropriate hormone or hormone mixture is contacted with the subject's
skin for a period of time sufficient to permit a therapeutically effective
amount of the hormone or mixture of hormones to be absorbed through the
skin into the subject's bloodstream.
The amount of progesterone in the blood which will be considered
therapeutically effective will, of course, vary from patient to patient,
and with the type of condition being treated. As a general rule, a
therapeutically effective amount can be considered the level of
progesterone one would anticipate during the second half of the luteal
phase of the menstrual cycle. However, other levels produced by the normal
functions of the body may also be effective, depending on the
circumstances. For example, a mean serum level of 2 ng/ml progesterone
gives an optimal effect in the treatment of menopause using a combination
of progesterone and estrogen.
According to W. S. Maxon (1987, "Use of Progesterone in the Treatment of
PMS, " J. Clin. Obstetrics & Gynecology 30 (2): 465-480), the adrenal
gland produces small amounts of progesterone from cholesterol and
pregenelone as an intermediate in the biosynthesis of corticosteroids.
During the proliferative phase of the menstrual cycle, most of the
circulating progesterone is adrenal in origin and is produced in
quantities of about 0.75 mg/day. During the follicular phase, serum
concentrations of progesterone range between 0.1 and 1 ng/ml.
During the luteal phase, progesterone production by the ovarian corpus
luteum dramatically increases and may reach 50 mg per day. When the
conceptus is expected to implant during the mid-luteal phase, serum
concentrations of progesterone average 5 to 25 ng/ml. Progesterone is
released in a pulsatile fashion, which correlates with LH pulsatility.
During pregnancy the placenta contributes an additional 25 to 40 mg/day of
progesterone. Concentrations during gestation increase progressively to a
mean of 175 ng/ml at term.
Thus, blood level of progesterone can fluctuate widely during the luteal
phase of the cycle, i.e. at least from 0-50 ng/ml. Generally, however, the
fluctuation is on the order of 0-18 ng/ml. The preferred method of
assaying the level of progesterone in the blood is by standard
radioimmunoassay, which is well known to those skilled in the art.
Compositions of the present invention are also useful for treating vaginal
conditions such as yeast infections and vaginal dryness. Compositions of
the present invention are also useful as spermicides. For example,
compositions of the present invention comprising a drug selected from
butylurea and butaconazole can be used to treat vaginal yeast infections.
Compositions of the invention comprising butylurea can also be used as
spermicides. Compositions of the present invention, with or without
drug(s), may be used to treat vaginal dryness.
Compositions of the present invention comprising progesterone, estrogen,
progestin, testosterone and a mixture of any two or more of the foregoing
may also be administered vaginally to treat a variety of vaginal or
gynecological conditions.
Accordingly, the present invention provides methods for treating vaginal
yeast infections. The present invention also provides methods for treating
vaginal dryness. The invention also provides methods for contraception
which involve the vaginal administration of compositions of the present
invention comprising urea or urea derivatives such as butylurea. These
methods involve the placement of a composition of the present invention
inside the vagina of a subject.
5. EXAMPLES
5.1 MANUFACTURE OF A PREFERRED COMPOSITION OF THE INVENTION
A hydrogel-forming base mixture of the invention is prepared a by mixing
together the following seven dry powder ingredients:
63% methyl cellulose
21% guar gum
5% glucose
3% pectin
1.5% sodium chloride
3.5% propylparaben
3% methyl paraben
After mixing the above ingredients, the mixture is micronized to a size of
approximately one micron.
A composition for the transdermal delivery of natural progesterone
containing the ingredients:
2% butylurea
9% base mixture hydrogel powder
10% progesterone
20% propylene glycol
59% distilled water
is prepared as described below.
Mix the hydrogel, butylurea and progesterone powders with the propylene
glycol forming a paste. Warm (do not boil) the paste until the ingredients
totally dissolve and the paste becomes a thinned pourable liquid. Use a
large enough container to accept the combined volume of thinned paste and
tepid water. Cold or hot water may be used to delay or accelerate the
set-up time. Place the container with water in a stirring unit using a
blade-type prop. Begin stirring water at a speed to form a vortex at the
surface. Add all the combined warmed glycol mixture to the stirring water.
Continue to mix for 3 to 15 minutes or until the proper or desired
viscosity is achieved. Place a cover over the finished mixture to prevent
short term evaporation. To prevent long-term evaporation, remove the
finished mixture from the container and place in a vapor barrier
container. Shelf life in the container should be several years.
5.2 SKIN PERMEATION ASSAYS
5.2.1 MATERIALS AND METHODS
Materials
Excised full-thickness human skin was obtained from elective surgery,
(e.g., breast reductions) or occasionally, from amputated legs. The tissue
was stored in plastic containers at refrigerator temperature until use, at
which time the subcutaneous fat and connective tissue were carefully
trimmed off. Skin specimen thickness was in the range 1.5-2.0 mm, with
characteristic histological features preserved.
Tritium-labeled progesterone was obtained from NEN-DuPont (Wilmington,
Del.), with the label at ring positions 1, 2, 6, and 7. It was
incorporated in the test compositions in the range 100 to 500 DPM
(Disintegration Per Minute) per microgram of progesterone. The labeled
progesterone was incorporated at the pre-polymerization stage, i.e., just
as water is added to form the hydrogel polymer. Aliquots of the gelling
mixtures were added to small amounts of tritiated progesterone in
scintillation vials (after the solvent had been evaporated), and stirred
briskly with a small spatula. The vials were then tightly capped and
stored at room temperature. Milligram portions of this mixture were then
taken from widely-spaced sites from within the vials, rapidly weighed, and
dispersed in scintillation cocktail for determination of specific
activities.
Transdermal Penetration
Transdermal penetration was performed in a single-chamber,
solvent-replacement Diffusion Cell, held vertically and inverted (FIG.
13). Half-inch diameter discs of skin to which nylon washers had been
cemented with cyanoacrylate were used. The available diffusional area of
each skin disc enclosed by the nylon washer was 0.495 cm.sup.2. The cell
was assembled from parts of a commercial PVC coupling manufactured by
Genova Products, Inc., Davison, Mich. The body of the coupling serves as
the receptor chamber. The skin disc (5), kept flat by the nylon washer (6)
cemented to its surface, is seated in the bottom end of the chamber,
dermal side in contact with the receptor fluid (8). After test material is
applied to the skin surface, an O-ring (4) and a flanged PVC washer (2)
coated with aluminum foil (3) are positioned under the nylon washer on the
skin, and a retaining nut (1) is carefully tightened under all. A small,
teflon-covered magnetic stirring button (7) and the receptor fluid are
introduced, after which the top end of the coupling is stoppered with
another foil-coated flanged washer (9). After assembly, the cell is held
in a rack on a magnetic stirrer, in a 32.degree. C. incubator. The
magnetic stirring button is used to stir the receptor fluid in the
inverted cell, and this button spins in direct contact with the dermal
side of the skin. In this configuration, the 1 ml of fluid in the receptor
chamber is mixed instantaneously as stirring is begun, and continuously
during the course of the experiment. The receptor fluid was physiological
saline, and 0.5 ml samples were removed (with replacement) at one-hour
intervals.
Intradermal Penetration
Intradermal penetration was assessed with 0.5-inch diameter discs of skin,
to which nylon washers were cemented, as described above. Discs with
attached washers were placed in wells drilled in a plastic block. The
block was then covered with a sheet of clear plastic to minimize
dehydration of the skin. To terminate penetration, individual discs were
removed from the block, and residual material removed from the surface by
a rinse/wipe procedure as follows: 1) a stream of ice-cold water was
delivered to the skin surface confined within the washer for 10 seconds,
and the surface then dried with absorbent paper. These steps were
repeated, and then 2) a smaller disc of skin was punched out from within
the cleansed area, and 3) dissolved for determination of tritiated
progesterone. Dissolution was in 1N NaOH for an hour at 100.degree. C.
followed by neutralization of the alkali solution with perchloric acid. If
the epidermis was to be separated from the dermis for measurement of
radioactivity, this separation was done by exposing the disc to an
infrared heat lamp, held at 4 inches from the surface for 30 seconds, and
peeling off the epidermis with fine forceps. Scintillation cocktail was
added to the dissolved tissue samples, for determination of radioactivity.
Thirteen formulations were used in the Examples described hereinbelow. The
formulations were prepared as described above by addition of radioactive
progesterone during polymerization, before the final viscosity had
developed. The thirteen formulations are give below. The hydrogel-forming
base mixture used in all thirteen formulations consisted of: 63% methyl
cellulose, 21% guar guam, 5% glucose, 3% pectin, 1.5% sodium chloride,
3.5% propyl paraben, and 3% methyl paraben.
Sample A-1 Sample B-1 Sample C-1
20% propylene glycol 20% propylene glycol 20% propylene glycol
4% natural 4% natural 4% natural
progesterone progesterone progesterone
13% hydrogel-forming 13% hydrogel-forming 13% hydrogel-forming
base mixture base mixture base mixture
3% oleic acid 3% oleic acid 3% oleic acid
60% water 59% water 59% water
Sample A-2 Sample B-2 Sample C-2
20% propylene glycol 20% propylene glycol 20% propylene glycol
4% natural 20% natural 20% natural
progesterone progesterone progesterone
13% hydrogel-forming 13% hydrogel-forming 14% hydrogel-forming
base mixture base mixture base mixture
3% Myristic acid 3% Myristic acid 1.5% Myristic acid
60% water 40% water 44.5% water
Sample A-3 Sample B-3 Sample C-3
20% propylene glycol 20% propylene glycol 20% propylene glycol
4% natural 4% natural 4% natural
progesterone progesterone progesterone
13% hydrogel-forming 14% hydrogel-forming 14% hydrogel-forming
base mixture base mixture base mixture
3% n-butylurea 6% n-butylurea 1.5% n-butylurea
60% water 56% water 60.5% water
Sample W Sample X
20% propylene glycol 20% propylene glycol
5% natural progesterone 10% natural progesterone
13% hydrogel-forming base mixture 13% hydrogel-forming base mixture
1.5% n-butylurea 1.5% n-butylurea
60.5% water 55.5% water
Sample Y Sample Z
20% propylene glycol 20% propylene glycol
15% natural progesterone 20% natural progesterone
11% hydrogen-forming base mixture 9% hydrogel-forming base mixture
1.5% n-butylurea 2.5% n-butylurea
52.5% water 48.5% water
5.2.2 PROGESTERONE PENETRATION THROUGH A DIALYSIS MEMBRANE
Since the transdermal progesterone experiments were to be performed using
physiological saline as the receptor fluid, it was first determined if
penetration might be limited by solubility of progesterone in the
physiological saline. Thus, penetration of progesterone through a dialysis
membrane, which was assumed to be more permeable than the skin, was
measured to see how much progesterone could accumulate in the receptor of
the diffusion cells. The dialysis membrane used was Spectra/Por.sup.R No.
1 dialysis tubing, purchased from Thomas Scientific, Swedesboro, N.J. The
dialysis membrane was positioned in the diffusion cell as described above.
The results are given in FIG. 14, which is a plot of the cumulative amount
of progesterone penetrated (.mu.g/cm.sup.2) over a period of about 1.5
hours. FIG. 14 shows that penetration occurred at a rate of about 30
.mu.g/cm.sup.2 /Hr. Note that there appeared to be no lag time, i.e., the
rate of penetration appeared to be linear from the time of contact. Such a
time course for penetration is consistent with diffusion through pores
(i.e., the solvent-filled pores of the dialysis membrane).
5.2.3 TRANSDERMAL PENETRATION OF PROGESTERONE: COMPARISON OF COVERED AND
NOT-COVERED SAMPLES
Using Sample A-1, rates of progesterone penetration through the skin were
compared for covered with a layer of aluminum foil vs. not-covered
samples. FIG. 15 shows a plot of the cumulative amount of progesterone
penetration (.mu.g/cm.sup.2) over a period of about 8 hours for uncovered
and covered samples of A-1. Clearly, penetration proceeds more rapidly
through the skin when the application site is covered. Also note that
there is a lag time, i.e., the steady-state rate of progesterone
penetration was not established until 2-3 hours after application. This
kind of time course is consistent with the drug having to partition into
(dissolve in) the skin before the transdermal diffusional process begins.
5.2.4 TRANSDERMAL PENETRATION OF PROGESTERONE: COMPARISON OF OLEIC ACID
MYRISTIC ACID AND BUTYLUREA PENETRATION ENHANCERS
Rates of transdermal penetration of progesterone were determined for three
samples: A-1, A-2, and A-3. Each of these samples was of the same
viscosity, but each contained a different kind of penetration enhancer.
(The compositions of these samples are given above in Section 6.2.1). The
penetration data for samples A-1, A-2 and A-3 are given in Table 1.
TABLE 1
Transdermal Penetration of Progesterone
.mu.g/cm.sup.2
Hrs
1 2 3 4 5 6 7 8
Sample A-3
Skin #1* 1.3 3.9 9.2 18.0 28.0 37.4 48.2 57.6
Skin #2 0.49 5.8 14.8 28.6 46.0 63.7 82.9 105.2
Skin #3 4.5 13.3 25.0 37.1 49.8 63.7 77.0 92.3
Steady-state Rates, .mu.g/cm.sup.2 /HR: #1 = 9.8, #2 = 18.1, #3 = 13.4
Sample A-2
Skin #1 0.29 0.97 1.8 4.1 5.6 7.7 9.7 11.5
Skin #2 0.35 1.2 2.6 5.1 8.0 11.3 14.6 18.9
Steady-state Rates, .mu.g/cm.sup.2 /HR: #1 = 1.9, #2 = 3.2
Sample A-1
Skin #1 0.53 1.4 2.9 5.4 8.7 11.9 14.6 18.4
Skin #2 3.4 7.9 12.6 16.9 21.8 26.4 31.1 36.3
Steady-state Rates, .mu.g/cm.sup.2 /HR: #1 = 1.9, #2 = 3.2
As may be seen in Table 1, n-butylurea was clearly the most efficacious of
the three in promoting the penetration of progesterone through the skin.
The highest rate observed, (18.1 .mu.g/cm.sup.2 /Hr, sample A-3, skin #1)
was for the composition of the present invention containing n-butylurea.
Note that the rate of 18.1 .mu.g/cm.sup.2 /Hr was substantially lower than
that measured through dialysis membrane (Section 6.2.2). Thus, the test
system does not impose an upper limit on the rate of penetration, and
therefore, the measured rates are a true indication of how fast the drug
can be transferred through the skin from these formulations.
Some of the data from these determinations are plotted in FIG. 16, to
illustrate how the rates were determined. A linear regression analysis was
performed for each of the three curves, corresponding to samples A-1, A-2
and A-3, respectively, using the points taken in the interval from 3-8
hours. The rates were derived from the slopes of the curves. The rate is
defined as the slope of the plot of the cumulative amount of progesterone
penetrated in .mu.g/cm.sup.2, versus time in hours. It may be seen that
the plots are almost perfectly linear during this interval (regression
coefficient >0.99). The position of the x-intercepts indicates that there
was a lag time of about two hours. Table 2 gives the 3-8 hour steady state
rates, the average for hours 1-8 of penetration and the average rates for
hours 8-30 of penetration for samples A-1, A-2 and A-3. It is also clear
from the data in Table 2 that the rate of penetration measured in the
first eight hours of contact with the skin was sustainable for more than a
day (30 Hrs in this experiment).
TABLE 2
Maintenance of the Rate of Progesterone Penetration (.mu.g/cm.sup.2 /Hr)
(Skin #1)
Steady-state, 3-8 Hrs Av. Rate, 1st 8 hrs Av. Rate, 8-30 Hrs
A-1 3.1 3.3 1.2
A-2 1.9 1.7 1.6
A-3 9.8 9.1 8.9
* Skin Donor Number, #1, #2, etc.
5.2.5 INTRADERMAL PENETRATION OF PROGESTERONE: COMPARISON OF OLEIC ACID,
MYRISTIC ACID AND BUTYLUREA PENETRATION ENHANCERS
Since it had been observed that dilution of the receptor fluid seemed to
decrease transdermal penetration, samples A-1, A-2, A-3, B-1, B-2, B-3,
C-1, C-2, and C-3 were compared by measuring intradermal penetration
rather than transdermal penetration. The observed dilution-dependent
decrease in transdermal penetration was contrary to expectation, since
normally, lowering drug concentration the receptor increases penetration,
as it increases the concentration gradient across the skin. The decrease
was especially unexpected because in this model, the receptor volume is at
a minimum (only the fluid in the dermal compartment of the skin).
All measurements were performed on skin from a single donor. Results are
given in Table 3.
TABLE 3
Intradermal Penetration of Progesterone, over 20 Hrs, .mu.g/cm.sup.2
Sample Full-thickness Dermis
A-1 71.4 36.3
A-1* 47.3 29.0
A-2 72.6 33.6
A-3 44.5 34.0
B-1 91.0 19.6
B-2 59.1 40.0
B-3 54.5 37.0
C-1 50.5 33.0
C-2 71.0 619.6
C-3 56.5 27.6
Mean, +/-SD 61.8, +/-14.4 31.0, +/-7.0
As Table 3 shows, a mean value of about 60 .mu.g/cm.sup.2 could be
recovered from "full thickness" skin after a 20-hr contact period, and
about 30 .mu.g/cm.sup.2 from the dermal portion of the skin, the site of
the dermal capillary network. These numbers indicate that only about 3
.mu.g/cm.sup.2 /Hr penetrated the skin when there was no added receptor
fluid in contact with the dermis, and that about half the penetrating
material actually got into the dermis, i.e., under these circumstances,
about 1.5 .mu.g/cm.sup.2 /Hr of progesterone was "available" for uptake
into the capillaries. Further, the rate of differences observed with
different enhancers in the first set of comparisons (Section 6.2.4, Table
1, FIG. 16), could not be demonstrated.
5.2.6 TRANSDERMAL PENETRATION OF PROGESTERONE: COMPARISON OF OLEIC ACID AND
BUTYLUREA PENETRATION ENHANCERS
Transdermal penetration using samples A-3 and C-3 was measured using skin
from the same donor as was used in Section 6.2.5. Measurements were
performed in two ways: with the sampling from the diffusion cells during
the first eight hours, and without such sampling (Table 4). In this
experiment, the amounts that passed through the skin were much higher when
the diffusion cells were not sampled, however the best hourly average for
transdermal penetration rate (Sample C-3, 4.8 .mu.g/cm.sup.2 /Hr), was
still only about one-half the lowest rate measured with n-butylurea in
Section 6.2.4 (Table 1).
TABLE 4
Transdermal and Intradermal Penetration of
Progesterone over 20 Hrs, .mu.g/cm.sup.2
A-3 A-3** C-3 C-3**
Transdermal 36.0 56.0 28.1 95.5
Intradermal, Dermis 23.0 81.4
Intradermal, Epidermis 18.6 20.3
* A duplicate of Sample A-1.
**These cells were not sampled, whereas the other member of each pair, (A-3
and C-3) were sampled during the first eight hours.
5.2.7 TRANSDERMAL PENETRATION OF PROGESTERONE USING BUTYLUREA PENETRATION
ENHANCER: COMPARISON OF VISCOSITIES
To access the effect of viscosity on transdermal penetration rate, rates
were measured using samples of low viscosity (A-3) and high viscosity
(C-3), both containing n-butylurea. The results, presented in Table 5,
indicated that in the range tested, viscosity did not affect the
transdermal penetration rate. It is also clear that penetration rates
through these skin samples (average 9-10 .mu.g/cm2/Hr) were higher than
the best rate shown in Table 4, providing some indication that the skin
used in Section 6.2.5 for measurements of intradermal penetration and in
Section 6.2.6 for transdermal penetration may have been atypically low
permeability.
TABLE 5
Transdermal Penetration Progesterone, .mu.g/cm.sup.2 /HR
(20-Hr Assay, w/o Hourly Sampling)
Test Article A-3 C-3
Skin # I II I II
7.8 10.4 8.9 11.2
9.4 11.9 6.7 11.4
7.2 9.5 9.8 10.0
Mean SD 8.13 10.56 8.47 10.87
1.14 1.16 1.59 0.75
Mean, All Samples SD 9.35 9.67
1.68 1.72
5.2.8 TRANSDERMAL PENETRATION OF PROGESTERONE: EFFECT OF PROGESTERONE
CONCENTRATION
To access the effect of progesterone content of the inventive compositions
upon transdermal penetration, tests were carried out using samples W, X, Y
and Z in which the progesterone concentration was varied from 5 to 20%.
The results are give in Table 6.
TABLE 6
Transdermal Progesterone Penetration
Initial and sustained Rates, in .mu.g/cm.sup.2 /Hr
Skin No.
I II III
Progesterone Rate
Sample Conc., (%) Initial 0-24 Hr 24-48 Hr Initial Initial
W 5 5.2 4.9 5.0 4.7 6.2
X 10 6.7 6.1 6.0 5.8 8.1
Y 15 7.8 7.0 7.3 6.5 9.0
Z 20 11.1 10.4 10.0 10.5 13.6
As may be seen in Table 6, a 4-fold increase in concentration resulted in a
doubling of the penetration rate, both initially, and in the rate
sustainable for up to 48 hours. While the concentration dependency appears
to be real, it should be noted that the highest rate observed here (about
14 .mu.g/cm.sup.2 /hr) was not higher than the 18.1 .mu.g/cm.sup.2 /Hr
rate seen with a 5% progesterone formulation in Section 6.2.4 (see Table
1). This disparity may be due to skin-to-skin variation.
5.2.9 TRANSDERMAL PENETRATION OF PROGESTERONE: COMPARISON OF FULL-THICKNESS
SKIN AND SKIN FROM WHICH THE EPIDERMIS HAD BEEN REMOVED
The transdermal penetration of the progesterone through full-thickness skin
was compared to penetration through skin from which the epidermis had been
removed. The rate increased only about 2-fold after this maneuver,
indicating that the dermis is an important factor in limiting the rate of
penetration through the skin.
5.3 DEMONSTRATION OF INTRADERMAL PENETRATION OF PROGESTERONE BY
AUTORADIOGRAPHY
Introduction
It was not possible to demonstrate progesterone within the skin by
conventional histological techniques, as it appeared to be extracted by
the alcohols used in processing. Therefore, an alternative procedure was
used to acquire skin surface biopsies (Marks and Dawber, 1971, Brit. J.
Dermatol. 85:117-123). Surface biopsies consist of a sheet of the top 2-3
layers of the stratum corneum, which retain vellus hairs on the underside,
along with fragments of the pilosebaceous ducts known as "follicular
casts" (Lavker and Leyden, 1979, "Lamellar Inclusions in Follicular Horny
Cells: A New Aspect of Abnormal Keratinization," J. Ultrastruct. Res. 69:
362-370). These samples are produced by application of a drop of
cyanoacrylate adhesive on a microscope slide to the surface of the skin,
and after the adhesive sets, the slide with adhering tissue is carefully
peeled off. When surface biopsy samples were taken from skin to which
radioactive progesterone had been applied, a time-dependent accumulation
of progesterone in the tissue could be demonstrated, by autoradiography.
Procedure
Discs of skin were prepared as described in "Methods", for measurement of
intradermal penetration, but using much larger washers to provide test
sites of about 10 cm.sub.2 in area. A test formula containing 20%
progesterone (Sample Z) was applied, and uptake into the skin was allowed
to proceed for one hour, and for 20 hours. Surface residue was removed at
the indicated times, using the rinse/wipe procedure described. Skin
surface biopsies were taken from 1 & 20-Hr skin discs, and coated with
photographic emulsion (Illford K-2 emulsion, Illford, London), then
allowed to develop for 14 days. Rinsing and fixing were done as prescribed
by the manufacturer.
Results
Three surface biopsies were photographed with black-and-white film, on a
white background, with sub-surface illumination. There was a distinct
gradation in grayness, increasing from the baseline level of the control
sample to the 20-Hr sample, as would be expected with increasing numbers
of silver grains. It is clear that the stratum corneum as a whole darkened
with time, but the follicular fragments were much darker than the
interfollicular stratum corneum, indicating a preferential accumulation of
progesterone in the pilosebaceous follicles. This pattern was also obvious
when sections were photographed with incident light. Ridges and grooves
that crisscrossed the undersurface were visible; these are the "negative"
of the fine folds on the surface of the skin. A high magnification study
of the sections was undertaken, to establish that the pattern of darkness,
or opacity, seen in these low-magnification images was really due to
silver grains. A view of the underside of a control biopsy, showed an
uprooted vellus hair enveloped by a mixture sebum and compacted
corneocytes (keratinized stratum corneum cells). It resembled a horn with
a collar, emerging from the background undersurface of the stratum
corneum.
The horn is the coated hair, and the collar a portion of the infundibulum,
or funnel-shaped opening of the pilosebaceous duct, that emerges on the
surface of the skin. The polygonal outlines of individual corneocytes are
sometimes discernible, a convenient metric (about 40 microns) for the
scale of the images. In distinct contrast to a control section, the
underside of a section from skin which had been in contact with a
tritiated 20% progesterone formula for 20 hours appeared to be stained a
deep blue color, most intensely at follicular structures. At higher
magnification, the blue stain could be resolved into individual silver
grains, seen as a stippling of blue dots about 500 nanometers in diameter.
Where the wall of the follicle was perpendicular to the plane of the
section (W), the stain was much more intense, a combination of a higher
grain density, and effectively viewing a thicker section (imagine looking
at the edge of a piece of stained glass). An image of a 0.2 mm-long
follicular fragment showed that progesterone was distributed uniformly to
this depth within the lipid-rich interior of the follicle. Finally,
stippling (and thus silver grains) was absent from a control biopsy, taken
from tissue which had never been in contact with radioactive material.
Summary
The disposition of tritiated progesterone in the surface biopsies examined
is consistent with diffusion through the follicles, as well as diffusion
through the interfollicular stratum corneum. Accumulation in the follicles
appeared to be faster than in the stratum corneum, but both were shown to
be time-dependent. The contribution of each route to the combined rate of
penetration is not easily determined, but it should noted that the surface
area of the openings of the follicles is estimated to be only about 0.001%
of the area in contact with the applied test formulation (about 30
follicles per cm.sup.2, and about 100 micron.sup.2 per follicle). To have
a real impact under these circumstances, movement through the follicular
"shunt" route would have to be more than four orders of magnitude faster,
per unit area. If, however, we invoke the length of the follicular shunts,
the real interfacial area (follicle/dermis) could approach 1%, and under
these circumstances, if the transfer rate from follicle to dermis were
only 10 times as fast (or more) as the transfer rate from stratum corneum
to dermis, then the shunt route could approach or even exceed the
contribution of the transepidermal route to the total rate of penetration.
The Examples above demonstrate that progesterone penetration rates using
compositions of the present invention are in the range 1-20 .mu.g/cm.sup.2
/hr, and appear to be sustainable for at least 48 hours (Table 6). The
rate at the higher end of this range is in excess of two orders of
magnitude greater the 1.2 .mu.g/cm.sup.2 /day rate reported by Guy et al.,
(1987, "Kinetics of Drug Absorption Across Human Skin In Vivo," Pharmacol.
Skin 1: 70-76). (discussed supra). Although Barry and Bennett, (1987,
"Effect of Penetration Enhancers on the Permeation of Mannitol,
Hydrocortisone, and Progesterone Through Human Skin," J. Pharm. Pharmacol.
39: 535-546), reported somewhat higher rates when certain permeation
enhancers were used (supra), that method of application increases delivery
by pretreatment of skin with acetone and thus that method of application
to the skin is not amenable to a transdermal delivery patch system. Thus,
the compositions of the present invention provide unexpectedly superior
delivery to the blood of the hormone contained within them and a very
promising aspect of a sustained-released transdermal delivery system for
progesterone.
The present invention is not to be limited in scope by the specific
embodiments and examples described herein. Indeed, various modifications
of the invention in addition to those described herein will become
apparent to those skilled in the art from the foregoing description and
accompanying figures. Such modifications are intended to fall within the
scope of the appended claims.
Various publications are cited herein, the disclosures of which are
incorporated by reference in their entireties.
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