U.S. patent application number 12/268301 was filed with the patent office on 2009-03-12 for pharmaceutical compositions of 5-alpha-reductase inhibitors and methods of use thereof.
Invention is credited to Dario Norberto R. Carrara, Arnaud Grenier.
Application Number | 20090069364 12/268301 |
Document ID | / |
Family ID | 34520020 |
Filed Date | 2009-03-12 |
United States Patent
Application |
20090069364 |
Kind Code |
A1 |
Carrara; Dario Norberto R. ;
et al. |
March 12, 2009 |
PHARMACEUTICAL COMPOSITIONS OF 5-ALPHA-REDUCTASE INHIBITORS AND
METHODS OF USE THEREOF
Abstract
Non-occlusive compositions for transdermal delivery of
5-alpha-reductase inhibitors, and more particularly finasteride or
dutasteride or pharmaceutically acceptable salts or derivatives
thereof, and methods of making same. The composition may, for
example, be a gel suitable for transdermal or transmucosal
applications. The compositions of the present invention typically
include a mixture of water and alcohol, and a solvent system having
a mono alkyl ether of diethylene glycol and a glycol present in
specified ratios and in specific amounts, wherein the pH of the gel
is usually between about pH 4.5 and about pH 8. The compositions
may include further components, for example, the hydroalcoholic
vehicle may further include additional penetration enhancer(s),
buffering agent(s), antioxidant(s), stabilizer(s) and/or gelling
agent(s). Also, a method for the sustained delivery of
5-alpha-reductase inhibitors to treat a variety of conditions and
disorders.
Inventors: |
Carrara; Dario Norberto R.;
(Oberwil, CH) ; Grenier; Arnaud;
(Steinbrunn-Le-Haut, FR) |
Correspondence
Address: |
WINSTON & STRAWN LLP;PATENT DEPARTMENT
1700 K STREET, N.W.
WASHINGTON
DC
20006
US
|
Family ID: |
34520020 |
Appl. No.: |
12/268301 |
Filed: |
November 10, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11755923 |
May 31, 2007 |
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12268301 |
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11371042 |
Mar 7, 2006 |
7335379 |
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11755923 |
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PCT/EP04/11175 |
Oct 6, 2004 |
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11371042 |
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60510613 |
Oct 10, 2003 |
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Current U.S.
Class: |
514/284 |
Current CPC
Class: |
A61K 9/006 20130101;
A61P 5/28 20180101; A61P 5/32 20180101; A61K 47/32 20130101; A61K
47/10 20130101; A61K 9/0014 20130101; A61P 25/16 20180101; Y10S
514/947 20130101; A61P 5/26 20180101; A61K 47/08 20130101; A61K
9/7007 20130101; A61P 25/04 20180101; A61P 5/30 20180101; A61K 9/06
20130101; A61K 31/435 20130101; A61P 25/28 20180101; A61K 47/12
20130101; A61K 47/38 20130101; A61K 31/025 20130101; Y10S 514/946
20130101 |
Class at
Publication: |
514/284 |
International
Class: |
A61K 31/435 20060101
A61K031/435 |
Claims
1. A transdermal or transmucosal non-occlusive, semi-solid
pharmaceutical formulation comprising: at least one active
ingredient which is a 5-alpha-reductase inhibitor; and a permeation
enhancing solvent system present in an amount sufficient to
solubilize the active ingredient and characterized in that it
includes: (i) a pharmaceutically acceptable monoalkyl ether of
diethylene glycol present in an amount of between about 1% and 30%
by weight of the solvent system; (ii) a pharmaceutically acceptable
glycol present in an amount of between about 1% and 30% by weight
of the solvent system, wherein the monoalkyl ether of diethylene
glycol and the glycol in combination are present in an amount of at
least 15% and no more than 60% by weight of the formulation; and
(iii) a mixture of a C.sub.2 to C.sub.4 alcohol and water, which
mixture is present in an amount of between about 40% and 98% by
weight of the solvent system, wherein the C.sub.2 to C.sub.4
alcohol is present in an amount of about 5% to 80% by weight of the
mixture, and the water is present in an amount of about 20% to 95%
by weight of the mixture; so that, compared to formulations not
containing the present permeation enhancing solvent system, the
present formulation (a) inhibits crystallization of the at least
one active ingredient on a skin or mucosal surface of a mammal, (b)
reduces or prevents transfer of the formulation to clothing or to
another being, (c) modulates biodistribution of the at least one
active agent within different layers of skin, (d) facilitates
absorption of the at least one active agent by a skin or a mucosal
surface of a mammal, or (e) provides a combination of one or more
of (a) through (d).
2. The pharmaceutical formulation of claim 1, wherein the monoalkyl
ether of diethylene glycol and the glycol are present in a weight
ratio of 10:1 to 1:10.
3. The pharmaceutical formulation of claim 1, wherein the monoalkyl
ether of diethylene glycol is selected from the group consisting of
diethylene glycol monomethyl ether, and diethylene glycol monoethyl
ether or mixtures thereof.
4. The pharmaceutical formulation of claim 1, wherein the glycol is
selected from the group consisting of propylene glycol, dipropylene
glycol or mixtures thereof.
5. The pharmaceutical formulation of claim 1, wherein the C.sub.2
to C.sub.4 alcohol is selected from the group consisting of
ethanol, propanol, isopropanol, 1-butanol, 2-butanol, or mixtures
thereof.
6. The pharmaceutical formulation of claim 1, wherein the
formulation further includes a saturated fatty alcohol or fatty
acid, or mixtures thereof, wherein said fatty alcohol and/or said
fatty acid have the formula CH.sub.3--(CH.sub.2).sub.n--CH.sub.2OH
or CH.sub.3--(CH.sub.2).sub.n--H.sub.2COOH, respectively, in which
n is an integer from 8 to 22, preferably 8 to 12, most preferably
10; or an unsaturated fatty alcohol or fatty acid, or mixtures
thereof, wherein said unsaturated fatty alcohol and/or fatty acid
have the formula CH.sub.3--(C.sub.nH.sub.2(n-x))--OH or
CH.sub.3--(C.sub.nH.sub.2(n-x))--COOH, respectively, in which n is
an integer from 8 to 22.
7. The pharmaceutical formulation of claim 1, wherein the
formulation further includes lauryl alcohol or myristyl alcohol
present in an amount from 0.1 to 2% by weight of the total
formulation.
8. The pharmaceutical formulation of claim 1, wherein the at least
one active ingredient is an azasteroid compound.
9. The pharmaceutical formulation of claim 1, wherein the
azasteroid compound is used to treat benign prostate hyperplasia;
prostate cancer; or androgenetic alopecia.
10. The pharmaceutical formulation of claim 9, wherein the
azasteroid compound is selected from the group consisting of
finasteride and pharmaceutically acceptable salts thereof.
11. The pharmaceutical formulation of claim 9, wherein the
azasteroid compound is selected from the group consisting of
dutasteride and pharmaceutically acceptable salts thereof.
12. The pharmaceutical formulation of claim 1, further comprising
an agent selected from the group consisting of gelling agents;
permeation enhancers, preservatives, anti-oxidants, buffers,
humectants, sequestering agents, moisturizers, surfactants,
emollients, film-forming agents, solubilizers, flavors, fragrances,
stabilizers, solubilizers, and any combination thereof.
13. The pharmaceutical formulation of claim 1, comprising
dutasteride in an amount of between about 0.01% and 5% by weight; a
monoethyl ether of diethylene glycol in an amount of between about
1% and 30% by weight; propylene glycol in an amount of between
about 1% and 30% by weight; a C.sub.2 to C.sub.4 alcohol in an
amount of between about 10% and 70% by weight; a fatty permeation
enhancer selected from the group of lauryl alcohol, myristyl
alcohol, oleyl alcohol, lauric acid, myristic acid, or oleic acid
in an amount of between about 0.1% to about 2% by weight; water;
and an agent selected from the group consisting of gelling agents;
permeation enhancers, preservatives, anti-oxidants, buffers,
humectants, sequestering agents, moisturizers, surfactants,
emollients, film-forming agents, solubilizers, flavors, fragrances,
stabilizers, solubilizers, and any combination thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of co-pending
application Ser. No. 11/755,923, filed May 31, 2007, which is a
continuation-in-part of application Ser. No. 11/371,042, filed Mar.
7, 2006, now U.S. Pat. No. 7,335,379, which in turn is a
continuation of International application PCT/EP2004/011175 filed
Oct. 6, 2004, which in turn claims the benefit of U.S. Provisional
Application No. 60/510,613, filed Oct. 10, 2003. The content of
each prior application is expressly incorporated herein by
reference.
TECHNICAL FIELD
[0002] The present invention relates to novel transdermal or
transmucosal pharmaceutical formulations, including compositions
and dosage forms, of dutasteride and its pharmaceutically
acceptable salts thereof, and a hydroalcoholic solvent system,
wherein the solvent system includes monoalkyl glycol ethers and
glycols in specific ratios.
[0003] Described herein are formulations that are useful and
efficacious for transdermal delivery, as well as methods of use and
methods of manufacturing for such formulations.
BACKGROUND OF THE INVENTION
[0004] Transdermal delivery, i.e. the ability to deliver
pharmaceuticals agents into and through skin surfaces, provides
many advantages over oral or parenteral delivery techniques. In
particular, transdermal delivery provides a safe, convenient and
non invasive alternative to traditional administration systems that
can provide a straightforward dosage regimen, relatively slow
release of the drug into a patient's system, and control over blood
concentrations of the drug. In contrast to oral administration,
transdermal delivery typically does not produce the plasmatic peaks
and valleys created by oral delivery and G.I. tract absorption.
Second, transdermal delivery causes no gastrointestinal irritation,
does not present restrictions around the time that the drug should
be administered or whether or not the patient may eat afterwards.
In particular, once-a-day transdermal delivery offers ease of use
and is convenient, without the requirement to remember to take a
drug at a specific time. Third, transdermal delivery improves
patient compliance for patients who cannot swallow medication, for
drugs with unpleasant taste and/or undergoing significant
metabolism in the liver; the resulting increased bio-availability,
which means that smaller doses may be used for the same drug, is
responsible for minimized side effects. In contrast to parenteral
administration, transdermal delivery typically does not cause pain
and/or anxiety associated with needles, and does not present the
risk of introducing infection to treated individuals, the risk of
contamination or infection of health care workers caused by
accidental needle-sticks and the risk of disposal of used
needles.
[0005] The advantage of transdermal delivery is particularly
enhanced in case of hydrophilic drugs, because of the molecular
nature of the G.I. tract. As a lipid membrane, the G.I. tract
possesses hydrophobic properties, thus the more hydrophilic a drug
is, and the more likely it is to be absorbed poorly through the
G.I. tract. A well known example of this problem is sodium
alendronate, a bisphosphonate, which needs to be administered in
very large doses because only a very small fraction of the drug
(about 0.6) % is absorbed indeed when administered orally (please
refer to FOSAMAX.RTM. Tablets and Oral Solutions Prescribing
Information, issued by Merck & Co., Inc., the entire content is
incorporated herein for information).
[0006] However, despite its clear advantages, transdermal delivery
also poses inherent challenges, in part because of the nature of
skin. Skin is essentially a thick membrane that protects the body
by acting as a barrier. Consequently, passive delivery through
intact skin necessarily entails the transport of molecules through
a number of structurally different tissues, including the stratum
corneum, the viable epidermis, the papillary dermis and the
capillary walls in order for the drug to gain entry into the blood
or lymph system. Each tissue features a different resistance to
penetration, but the stratum corneum is the strongest barrier to
the absorption of transdermal and topical drugs. The tightly packed
cells of the stratum corneum are filled with keratin. The
keratinization and density of the cells may be responsible for
skin's impermeability to certain drugs. Transdermal delivery
systems must therefore be able to overcome the various resistances
presented by each type of tissue.
[0007] In recent years, advances in transdermal delivery include
the formulation of skin penetration enhancing agents, also known as
permeation enhancers. Permeation enhancers are often lipophilic
chemicals that readily move into the stratum corneum and enhance
the movement of drugs through the skin. Energy-assisted skin
permeation techniques also have emerged to improve transdermal
delivery, including heat, ultrasound, iontophoresis, and
electroporation. But even with these methodologies, only a limited
number of drugs can be administered transdermally without problems
such as sensitization or irritation occurring.
[0008] Transdermal delivery is different from topical delivery.
Drugs administered transdermally are absorbed through skin or
mucous membranes and provide effects beyond the application site.
In contrast, purpose of a topical drug, e.g., antibiotic ointment,
anti-acne cream, hair-growing lotion, anti-itching spray, is to
administer medication at the site of intended action. Topical
medications typically should be designed not to permit significant
drug passage into the patient's blood and/or tissues. Topical
formulations are often used to treat infections or inflammations.
They also are used as cleansing agents, astringents, absorbents,
keratolytics, and emollients. The vehicle of a topical treatment,
i.e. the non-active component(s) that carries the active
ingredient(s), may interact with the active ingredient(s), changing
the drug's effectiveness. The vehicle may also cause skin
irritation or allergic reactions in some patients. Thus, the
vehicle must be selected with extreme care. Topical formulations
may be prepared as pastes, gels, creams, ointments, lotions,
solutions, or aerosols. Occlusion with household plastic wrap,
bandages, plasters, or plastic tape, is often used in conjunction
with topical treatments to improve the drug's absorption and its
effectiveness. Typically non-occlusive dosage forms are applied to
the skin or mucosa and are left uncovered and open in the
atmosphere. Because the non-occlusive dosage form is left
uncovered, unwanted transfer of the pharmaceutical formulation to
the clothing of the user or even to other individuals in close
proximity to the user is unavoidable. Other drawbacks of the
non-occlusive dosage form include evaporation of the formulation,
removal of the formulation from the skin or mucosa, for example, by
bathing or by other activities, and the non absorption of the
formulation through the skin, which is discussed below.
[0009] The inefficiencies of drug permeation across or through the
skin or mucosa barriers are known. It is also known that the
permeation of a drug in a non-occlusive transdermal or transmucosal
dosage form can be as little as 1% and usually is no more than 15%.
Thus, a vast majority of the active drug remains unabsorbed on the
skin or mucosa surface. Because the vast majority of the drug
remains on the skin and does not penetrate the skin or mucosa
surfaces, the bioavailability of the particular drug is not
optimal, and also a high risk of contamination of other individuals
in close proximity to the user is presented by the unwanted
transfer of the pharmaceutical formulation in the non-occlusive
dosage form.
[0010] Problems associated with the unwanted transfer of a
particular pharmaceutical formulation to others are well
documented. For example, Delanoe et al. reported the
androgenization of female partners of volunteers applying a
testosterone gel preparation during contraceptive studies (Delanoe,
D., Fougeyrollas, B., Meyer, L. & Thonneau, P. (1984):
"Androgenisation of female partners of men on medroxyprogesterone
acetate/percutaneous testosterone contraception", Lancet 1,
276-277). Similarly, Yu et al. reported virilization of a
two-year-old boy after incidental and unintentional dermal exposure
to a testosterone cream applied to his father's arm and back (Yu,
Y. M., Punyasavatsu, N., Elder, D. & D'Ercole, A. J. (1999):
"Sexual development in a two-year old boy induced by topical
exposure to testosterone", Pediatrics, 104, 23).
[0011] Moreover, the patient information brochure for ANDROGEL.RTM.
(1% testosterone gel from Unimed Pharmaceuticals Inc.) emphasizes
the potential for transfer of testosterone to other people and/or
clothing and the brochure includes safety measures to be taken by
the individual using the non-occlusive dosage form.
[0012] One way to overcome or minimize this contamination issue is
to physically protect the transdermal dosage form by covering skin
with the applied pharmaceutical formulation means of a patch
device, a fixed reservoir, an application chamber, a tape, a
bandage, a sticking plaster, or the like, which remain on the skin
at the site of application of the formulation for a prolonged
length of time. This is usually accomplished with occlusive dosage
forms.
[0013] Occlusive dosage forms present some advantages over
non-occlusive dosage forms such as assisting the rate of
penetration of drugs across the skin by maintaining the
thermodynamic activity of the drug close to its maximum (the
thermodynamic activity of a drug in a dermal formulation is
proportional to the concentration of the drug and the selection of
the vehicle, and according to the laws of thermodynamics, the
maximum activity of a drug is related to that of the pure drug
crystal). However occlusive dosage forms also exhibit several major
drawbacks. For example, occlusive dosage forms present a high
potential of local skin irritation caused by the prolonged contact
on the skin of the drug, volatiles, vehicle excipients, and the
adhesive used to attach the occlusive device, e.g., the patch, to
the skin. In addition, the occlusive nature of certain occlusive
dosage forms, such as the patch device, also restrict the natural
ability of the skin to "breathe," and thereby increases the risk of
irritation.
[0014] In addition to the aforementioned drawbacks of occlusive
dosage forms, significant serious hazards have been documented
regarding the high drug loading that is specific to patches. For
example, several cases of abuses with remaining fentanyl in
fentanyl patches have been reported. See, Marquardt K. A., Tharratt
R. S., "Inhalation abuse of fentanyl patch", J Toxicol Clin.
Toxicol. 1994; 32(1):75-8; Marquardt K. A., Tharratt R. S.,
Musallam N. A., "Fentanyl remaining in a transdermal system
following three days of continuous use.", Ann Pharmacother. 1995
October; 29(10):969-71; Flannagan L M, Butts J D, Anderson W H.,
"Fentanyl patches left on dead bodies--potential source of drug for
abusers.", J Forensic Sci. 1996 March; 41(2):320-1. Severe
incidental intoxication cases have also been documented. See
Hardwick Jr., W, King, W., Palmisano, P., "Respiratory Depression
in a Child Unintentionally Exposed to Transdermal Fentanyl Patch",
Southern Medical Journal, September 1997.
[0015] Patch products typically contain patient information, which
clearly indicate the risks discussed above. For instance,
OXYTROL.TM. (an oxybutynin patch commercialized by WATSON
Pharmaceuticals, Inc. USA) contains patient information that
indicates the following warning: "Since the patch will still
contain some oxybutynin, throw it away so that it can not be
accidentally worn or swallowed by another person, especially a
child." The high level of active drug residues is thus a critical
drawback of patches. Such accidents could not occur with the use of
gel formulations.
[0016] Although attempts have been made to overcome drawbacks
associated with both occlusive and non-occlusive drug forms, such
attempts have been futile. For example, as noted above, one
drawback of non-occlusive dosage forms is evaporation of the
formulation, which is left open in the atmosphere. The formulation
of non-occlusive supersaturated systems could have achieved an
ideal merge but transdermal formulations, which rely on
supersaturation technologies, present a major drawback of
formulation instability, both prior to and during application to
the skin due to solvent evaporation. See Davis A F and Hadgraft
J--Supersaturated solutions as topical drug delivery systems,
Pharmaceutical Skin Penetration Enhancement, Marcel Dekker Inc, New
York (1993) 243-267 ISBN 0 8247 9017 0, which is incorporated
herein by reference.
[0017] Notably, extraordinary physicochemical changes occur with
the evaporation of the solvent system, which result in
modifications of the concentration of the active agent, which may
even lead to drug precipitation, thereby altering the diffusional
driving force of the formulation. See Ma et al, Proceed. Intern.
Symp. Control. Rel. Bioact. Mater., 22 (1995). Consequently, the
percutaneous absorption of the active agent may be quite different
from that when the solvent was present.
[0018] In addition, controlling drug crystallization is of
particular interest for non-occlusive transdermal systems. Campbell
et al. resorted to a method of heating a crystalline hydrate to a
temperature above the melting point in order to prevent the
crystallization of the formulation. See, U.S. Pat. No. 4,832,953.
Ma et al found that PVP added to the matrix acts as an effective
crystallization inhibitor for norethindrone acetate transdermal
delivery systems. See, Int. J. of Pharm. 142 (1996) pp. 115-119).
DE-A-4210711 affirms that cholesterol and SiO.sub.2 are
crystallization inhibitors for 17-.beta.-estradiol transdermal
delivery system. WO 95/18603 describes soluble PVP as crystal
inhibitor for patch devices and affirms that soluble PVP increases
the solubility of a drug without negatively affecting the adhesion
or the rate of drug delivery from the pressure-sensitive adhesive
composition.
[0019] Additionally, the inhibition of crystallization in
transdermal devices was reported by Biali et al. See, U.S. Pat. No.
6,465,005 in which it is described that the use of a steroid
(estradiol for instance) as an additive in a process of manufacture
or storage of a transdermal device acts as a crystallization
inhibitor during storage of the device.
[0020] Further, transdermal delivery from semi-solid formulations
faces opposite requirements. The drug delivery system should enable
absorption of an extensive amount of active drug through the skin
within the shortest period of time in order to prevent
contamination of individuals, transfer to clothing or accidental
removing. The drug delivery system should also provide sustained
release of the active drug over 24 hours ideally, so that only
once-daily application is required. This drug delivery system
should also prevent drug crystallization at the application surface
area.
[0021] Drug delivery systems having such properties may be achieved
by combining various solvents. A volatile solvent may be defined as
a solvent that changes readily from solid or liquid to a vapor,
that evaporates readily at normal temperatures and pressures. Here
below is presented data for some usual solvents, where volatility
is reflected by the molar enthalpy of vaporization
.DELTA..sub.vapH, defined as the enthalpy change in the conversion
of one mole of liquid to gas at constant temperature. Values are
given, when available, both at the normal boiling point t.sub.b,
referred to a pressure of 101.325 kPa (760 mmHg), and at 25.degree.
C. (From "Handbook of Chemistry and Physics, David R. Lide,
79.sup.th edition (1998-1999)--Enthalpy of vaporization (6-100 to
6-115). Stanislaus et al. (U.S. Pat. No. 4,704,406 on Oct. 9, 2001)
defined as volatile solvent a solvent whose vapor pressure is above
35 mm Mg when the skin temperature is 32.degree. C., and as
non-volatile solvent a solvent whose vapor pressure is below 10 mm
Mg at 32.degree. C. skin temperature. Examples of non-volatile
solvents include, but are not limited to, propylene glycol,
glycerin, liquid polyethylene glycols, or polyoxyalkylene glycols.
Examples of volatile solvents include, but are not limited to,
ethanol, propanol, or isopropanol.
TABLE-US-00001 TABLE 1 Enthalpy of vaporization of certain solvents
t.sub.b .DELTA..sub.vapH (t.sub.b) .DELTA..sub.vapH (25.degree. C.)
Ethanol 78.3 38.6 42.3 Propan-2-ol (isopropanol) 82.3 39.9 45.4
Propanol 97.2 41.4 47.5 Butan-2-ol 99.5 40.8 49.7 Butan-1-ol 117.7
43.3 52.4 Ethylene glycol mono methyl ether 124.1 37.5 45.2
Ethylene glycol mono ethyl ether 135.0 39.2 48.2 Ethylene glycol
mono propyl ether 149.8 41.4 52.1 1,2-Propylene glycol 187.6 52.4
Not available Diethylene glycol mono methyl ether 193.0 46.6 Not
available Diethylene glycol mono ethyl ether 196.0 47.5 Not
available 1,3-Propylene glycol 214.4 57.9 Not available Glycerin
290.0 61.0 Not available
[0022] Numerous authors have investigated evaporation and
transdermal penetration from solvent systems. For Example, Spencer
et al. (Thomas S. Spencer, "Effect of volatile penetrants on in
vitro skin permeability", AAPS workshop held in Washington D.C. on
Oct. 31-Nov. 1, 1986) established that the relationship between
volatility and penetration is not absolute and depends on many
parameters such as for instance hydration of the tissue or the
solubility of the penetrant in the tissue. Stinchcomb et al.
reported that the initial uptake of a chemical (hydrocortisone,
flurbiprofen) from a volatile solvent system (acetone) is more
rapid than that from a non-volatile solvent system (aqueous
solution). With an aqueous solution, close to the saturation
solubility of the chemical, the driving force for uptake remains
more or less constant throughout the exposure period. Conversely,
for a volatile vehicle which begins evaporating from the moment of
application, the surface concentration of the chemical increases
with time up to the point at which the solvent has disappeared; one
is now left with a solid film of the chemical from which continued
uptake into the stratum corneum may be very slow and
dissolution-limited.
[0023] Risk assessment following dermal exposure to volatile
vehicles should pay particular attention, therefore, to the
duration of contact between the evaporating solvent and the skin
(Audra L. Stinchcomb, Fabrice Pirot, Gilles D. Touraille, Annette
L. Bunge, and Richard H. Guy, "Chemical uptake into human stratum
corneum in vivo from volatile and non-volatile solvents",
Pharmaceutical Research, Vol. 16, No 8, 1999). Kondo et al. studied
bioavailability of percutaneous nifedipine in rats from binary
(acetone and propylene glycol PG or isopropyl myristate IPM) or
ternary (acetone-PG-IPM) solvent systems, compared with the results
from simple PG or IPM solvent systems saturated with the drug.
(Kondo et al. S, Yamanaka C, Sugimoto I., "Enhancement of
transdermal delivery by superfluous thermodynamic potential. III.
Percutaneous absorption of nifedipine in rats", J Pharmaco Biodyn.
1987 December; 10(12):743-9).
[0024] U.S. Pat. No. 6,299,900 to Reed et al. discloses a
non-occlusive, percutaneous, or transdermal drug delivery
system--having active agent, safe and approved sunscreen as
penetration enhancer, and optional volatile liquid. The invention
describes a transdermal drug delivery system, which comprises at
least one physiologically active agent or prodrug thereof and at
least one penetration enhancer of low toxicity being a safe
skin-tolerant ester sunscreen. The composition comprises an
effective amount of at least one physiologically active agent, at
least one non-volatile dermal penetration enhancer; and at least
one volatile liquid.
[0025] U.S. Pat. No. 5,891,462 to Carrara discloses a
pharmaceutical formulation in the form of a gel suitable for the
transdermal administration of an active agent of the class of
estrogens or of progestin class or of a mixture thereof, comprising
lauryl alcohol, diethylene glycol mono ethyl ether and propylene
glycol as permeation enhancers.
[0026] Mura et al. describe the combination of diethylene glycol
mono ethyl ether and propylene glycol as a transdermal permeation
enhancer composition for clonazepam (Mura P., Faucci M. T.,
Bramanti G., Corti P., "Evaluation of transcutol as a clonazepam
transdermal permeation enhancer from hydrophilic gel formulations",
Eur. J. Pharm. Sci., 2000 February; 9(4): 365-72)
[0027] Williams et al. reports the effects of diethylene glycol
mono ethyl ether (TRANSCUTOL.TM.) in binary co-solvent systems with
water on the permeation of a model lipophilic drug across human
epidermal and silastic membranes (A. C. Williams, N. A. Megrab and
B. W. Barry, "Permeation of oestradiol through human epidermal and
silastic membranes from saturated TRANSCUTOL.RTM./water systems",
in Prediction of Percutaneous Penetration, Vol. 4B, 1996). Many
references may also illustrate the effect of TRANSCUTOL.TM. as an
intracutaneous drug depot builder well known to one skilled in the
art.
[0028] U.S. Pat. No. 5,658,587 to Santus et al. discloses
transdermal therapeutic systems for the delivery of alpha
adrenoceptor blocking agents using a solvent enhancer system
comprising diethylene glycol mono ethyl ether and propylene
glycol.
[0029] U.S. Pat. No. 5,662,890 to Punto et al. discloses
alcohol-free cosmetic compositions for artificially tanning the
skin containing a combination of diethylene glycol monoethyl ether
and dimethyl isosorbide as permeation enhancer.
[0030] U.S. Pat. No. 5,932,243 to Fricker et al. discloses a
pharmaceutical emulsion or microemulsion preconcentrate for oral
administration of macrolide containing a hydrophilic carrier medium
consisting of diethylene glycol mono ethyl ether, glycofurol,
1,2-propylene glycol, or mixtures thereof.
[0031] U.S. Pat. Nos. 6,267,985 and 6,383,471 to Chen et al.
disclose pharmaceutical compositions and methods for improved
solubilization of triglycerides and improved delivery of
therapeutic agents containing diethylene glycol mono ethyl ether
and propylene glycol as solubilizers of ionizable hydrophobic
therapeutic agents.
[0032] U.S. Pat. No. 6,426,078 to Bauer et al. discloses an oil-in
water microemulsion containing diethylene glycol mono ethyl ether
or propylene glycol as co-emulsifier of lipophilic vitamins.
[0033] Many research experiments have been carried out on
diethylene glycol mono ethyl ether (marketed under the trademark
TRANSCUTOL.TM. by Gattefosse) as an intracutaneous drug depot
builder. For example, Ritschel, W. A., Panchagnula, R., Stemmer,
K., Ashraf, M., "Development of an intracutaneous depot for drugs.
Binding, drug accumulation and retention studies, and mechanism
depot for drugs", Skin Pharmacol, 1991; 4: 235-245; Panchagnula, R.
and Ritschel, W. A., "Development and evaluation of an
intracutaneous depot formulation of corticosteroids using
TRANSCUTOL.RTM. as a cosolvent, in vitro, ex vivo and in-vivo rat
studies", J. Pharm. Pharmacology. 1991; 43: 609-614; Yazdanian, M.
and Chen, E., "The effect of diethylene glycol mono ethyl ether as
a vehicle for topical delivery of ivermectin", Veternary Research
Com. 1995; 19: 309-319; Pavliv, L., Freebern, K., Wilke, T.,
Chiang, C-C., Shetty, B., Tyle, P., "Topical formulation
development of a novel thymidylate synthase inhibitor for the
treatment of psoriasis", Int. J. Pharm., 1994; 105: 227-233;
Ritschel, W. A., Hussain, A. S., "In vitro skin permeation of
griseofulvin in rat and human skin from an ointment dosage form",
Arzneimeittelforsch/Drug Res. 1988; 38: 1630-1632; Touitou, E.,
Levi-Schaffer, F., Shaco-Ezra, N., Ben-Yossef, R. and Fabin, B.,
"Enhanced permeation of theophylline through the skin and its
effect on fibroblast proliferation", Int. J. Pharm., 1991; 70:
159-166; Watkinson, A. C., Hadgraft, J. and Bye, A., "Enhanced
permeation of prostaglandin E2 through human skin in vitro", Int.
j. Pharm., 1991; 74: 229-236; Rojas, J., Falson, F., Courraze, G.,
Francis, A., and Puisieux, F., "Optimization of binary and ternary
solvent systems in the percutaneous absorption of morphine base",
STP Pharma Sciences, 1991; 1: 71-75; Ritschel, W. A., Barkhaus, J
K., "Use of absorption promoters to increase systemic absorption of
coumarin from transdermal drug delivery systems",
Arzneimeittelforsch/Drug Res. 1988; 38: 1774-1777.
[0034] Thus there remains a need to provide a pharmaceutically
acceptable transdermal or transmucosal pharmaceutical formulation
or drug delivery system that exhibits the advantages of both
occlusive systems (high thermodynamic activity) and non-occlusive
systems (low irritation and sensitization potential, and excellent
skin tolerance) while overcoming the disadvantages of these
systems. The novel transdermal or transmucosal pharmaceutical
formulation of the present invention satisfies this need.
[0035] The present invention is directed to the transdermal
administration of 5-alpha reductase inhibitors. 5-alpha reductase
is an enzyme that converts testosterone, the male sex hormone, into
the more potent dihydrotestosterone (DHT). The 5-alpha reductase
exists as two isoenzymes, namely the steroid 5-alpha reductase 1
(SRD5A1) and the steroid 5-alpha reductase 2 (SRD5A2). The second
isoenzyme is deficient in 5-alpha-reductase deficiency which leads
to a form of intersexualism.
[0036] The enzyme 5-alpha reductase is produced only in specific
tissues of the male human body, namely the skin, seminal vesicles,
prostate and epididymis. Inhibition of 5-alpha reductase results in
decreased production of DHT, increased levels of testosterone and
possibly increased levels of estradiol.
[0037] 5-alpha-reductase inhibitor drugs are clinically used in the
treatment of conditions which are exacerbated by
dihydrotestosterone, such as mild-to-moderate benign prostatic
hyperplasia (BPH), prostate cancer and androgenetic alopecia (also
known as male-pattern baldness). In benign prostatic hyperplasia,
dihydrotestosterone acts as a potent cellular androgen and promotes
prostate growth--inhibiting the enzyme reduces the excessive
prostate growth. In alopecia, male-pattern baldness is one of the
effects of androgenic receptor activation. Reducing the levels of
DHT thus reduces alopecia. Finasteride inhibits the function of
only one of the isoenzymes (type 2), while dutasteride inhibits
both forms. These drugs decrease the levels of available
5.alpha.-reductase prior to testosterone binding with the enzyme,
thus reducing levels of DHT that derives from such a bond.
[0038] Adverse drug reactions experienced with 5.alpha.-reductase
inhibitors are generally dose-dependent. Common adverse drug
reactions include impotence, decreased libido, decreased ejaculate
volume. Rare adverse drug reactions include: breast tenderness and
enlargement (gynecomastia), and allergic reaction.
[0039] Thus there is a need for optimized delivery of
5-alpha-reductase inhibitor drug enhancing therapeutic effects
while reducing occurrence and/or importance of adverse drug
reactions associated with treatment with 5.alpha.-reductase
inhibitor drugs.
[0040] A variety of patents have disclosed compositions containing
5.alpha.-reductase inhibitor drugs such as finasteride or
dutasteride: see, e.g., U.S. Pat. Nos. 6,998,138; 6,974,569;
6,818,226; 6,733,776; 6,649,155; 6,630,164; 6,451,300; 6,271,246;
6,090,409; the entire content of which are incorporated herein as
reference.
[0041] No admission is made that any reference, including any
patent or patent document, cited in this specification constitutes
prior art. In particular, it will be understood that, unless
otherwise stated, reference to any document herein does not
constitute an admission that any of these documents forms part of
the common general knowledge in the art in United States of America
or in any other country. The discussion of the references states
what their authors assert, and the applicant reserves the right to
challenge the accuracy and pertinency of any of the documents cited
herein.
[0042] In view of the aforementioned, there remains a need to
provide a pharmaceutically acceptable transdermal or transmucosal
pharmaceutical formulation or drug delivery system containing
5-alpha-reductase inhibitors or pharmaceutically acceptable salts
thereof or pharmaceutically acceptable derivatives thereof that
exhibit the advantages of both occlusive systems (high
thermodynamic activity) and non-occlusive systems (low irritation
and sensitization potential, and excellent skin tolerance) while
overcoming the disadvantages of these systems. The novel
transdermal or transmucosal pharmaceutical formulation of the
present invention satisfies this need.
SUMMARY OF THE INVENTION
[0043] In one aspect, the present invention relates to non
occlusive compositions for pharmaceutical drug delivery. In one
embodiment, the composition may be formulated to be suitable for
transdermal application. The composition typically comprises a
therapeutically effective amount of 5-alpha-reductase inhibitors.
Further, the composition may be a lotion or a low-viscosity,
medium-viscosity, or high-viscosity gel. The composition typically
comprises a primary vehicle comprising a mixture of a mono alkyl
ether of diethylene glycol, a glycol, at least one short-chain
alcohol, water. Optionally, the composition also comprises a fatty
permeation enhancer. Preferred fatty permeation enhancers are
selected from the group of saturated fatty alcohols or fatty acids,
or mixtures thereof, and having the formula
CH.sub.3--(CH.sub.2).sub.n--CH.sub.2OH or
CH.sub.3--(CH.sub.2).sub.n--H.sub.2COOH, respectively, in which n
is an integer from 8 to 22, preferably 8 to 12, most preferably 10;
Some other preferred fatty permeation enhancers are selected from
the group of unsaturated fatty alcohols or fatty acids, or mixtures
thereof, and having the formula CH.sub.3--(C.sub.nH.sub.2(n-x))--OH
or CH.sub.3--(C.sub.nH.sub.2(n-x))--COOH, respectively, in which n
is an integer from 8 to 22. Most preferred fatty permeation
enhancers are lauryl alcohol and lauric acid, myristyl alcohol and
myristic acid, and oleyl alcohol and oleic acid, or mixtures
thereof.
[0044] In another embodiment of the present invention, the
compositions may include further components as described herein,
for example, the hydroalcoholic vehicle described herein above may
further comprise additional solvent(s), antioxidant(s),
cosolvent(s), penetration enhancer(s), buffering agent(s), and/or
gelling agent(s). The apparent pH of the composition is usually
between about pH 4.5 and about pH 8.5, and the composition is
designed for application to the surface of skin or of the
scalp.
[0045] Preferred embodiments of the present invention are low- to
medium-viscosity gel formulations for non-occlusive therapeutic
applications, with a viscosity ranging from 1,000 to 20,000
centipoises.
[0046] The formulations of the present invention may be provided,
for example, in unit dose container(s) or multiple dose containers
e.g., metering-dose dispensers.
[0047] In another aspect the present invention comprises a
composition for pharmaceutical drug delivery. Such compositions
may, for example, comprise a therapeutically effective amount of
5-alpha-reductase inhibitors, or a pharmaceutically acceptable salt
or derivative thereof, in a hydroalcoholic vehicle as described
herein above. In such compositions the transdermal flux of the
5-alpha-reductase inhibitor in the hydroalcoholic vehicle of the
present invention is greater than the transdermal flux of an equal
concentration of dutasteride in an essentially equivalent alcoholic
solution over an essentially equivalent time period, wherein the
skin acts as the flux rate controlling membrane.
[0048] In yet another aspect the present invention comprises a
composition for pharmaceutical drug delivery. Such compositions
may, for example, comprise a therapeutically effective amount of a
5-alpha-reductase inhibitor, or a pharmaceutically acceptable salt
or derivative thereof, in a hydroalcoholic vehicle. In such
compositions the transdermal flux of the dutasteride in the
hydroalcoholic vehicle of the present invention is independent from
the apparent pH of said compositions.
[0049] The above-described compositions for pharmaceutical delivery
may include further components as described herein, for example,
the hydroalcoholic vehicle may further comprise additional
solvent(s), antioxidant(s), cosolvent(s), penetration enhancer(s),
buffering agent(s), and/or gelling agent(s).
[0050] The compositions of the present invention may be used, for
example, for transdermal applications including application to the
skin (for example, arms, shoulders, scalp, thighs, abdomen) or to
the mucosal tissues (for example, intranasally, intrabucally, as an
ovule or as a suppository).
[0051] In yet another aspect, the present invention includes dosage
forms for pharmaceutical delivery of a drug, preferably a
5-alpha-reductase inhibitor such as, for example, finasteride or
dutasteride. In one embodiment, the dosage form is configured to
provide steady-state delivery of finasteride or dutasteride with
once-a-day dosing.
[0052] In a further aspect, the present invention includes methods
of manufacturing the compositions described herein for
pharmaceutical drug delivery.
[0053] In another aspect, the present invention includes methods
for administering a 5-alpha-reductase inhibitor to a subject in
need thereof. For example, the method may comprise providing a
composition of the present invention for transdermal,
pharmaceutical delivery of 5-alpha-reductase inhibitor. The
5-alpha-reductase inhibitor, and pharmaceutical salts or
derivatives thereof, can be used for the treatment of a variety of
conditions including, but not limited to, androgenetic alopecia,
benign prostate hyperplasia, or prostate cancer.
[0054] These and other embodiments of the present invention will
readily occur to those of ordinary skill in the art in view of the
disclosure herein.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0055] FIG. 1 shows data for equilibrium solubility of dutasteride
over a 16 hour permeation in various pure solvents;
[0056] FIG. 2 shows data for equilibrium solubility of dutasteride
over a 16 hour permeation in various hydro-alcoholic solvents;
[0057] FIG. 3 shows data for the effect of pH on equilibrium
solubility of dutasteride over a 16 hour permeation;
[0058] FIGS. 4 and 5 show data for equilibrium solubility of
dutasteride over a 16 hour permeation in various drug carriers
according to the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0059] All patents, publications, and patent applications cited in
this specification are herein incorporated by reference as if each
individual patent, publication, or patent application was
specifically and individually indicated to be incorporated by
reference in its entirety for all purposes.
[0060] It is to be understood that the terminology used herein is
for the purpose of describing particular embodiments only, and is
not intended to be limiting. As used in this specification,
description of specific embodiments of the present invention, and
any appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a cosolvent" includes two or more
cosolvents, mixtures of cosolvents, and the like, reference to "a
compound" includes one or more compounds, mixtures of compounds,
and the like.
[0061] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the invention pertains. Although
other methods and materials similar, or equivalent, to those
described herein can be used in the practice of the present
invention, the preferred materials and methods are described
herein.
[0062] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0063] The term "dosage form" as used herein refers to a
pharmaceutical composition comprising an active agent, such as
dutasteride, and optionally containing inactive ingredients, e.g.,
pharmaceutically acceptable excipients such as suspending agents,
surfactants, disintegrants, binders, diluents, lubricants,
stabilizers, antioxidants, osmotic agents, colorants, plasticizers,
coatings and the like, that may be used to manufacture and deliver
active pharmaceutical agents.
[0064] The term "gel" as used herein refers to a semi-solid dosage
form that contains a gelling agent in, for example, an aqueous,
alcoholic, or hydroalcoholic vehicle and the gelling agent imparts
a three-dimensional cross-linked matrix ("gellified") to the
vehicle. The term "semi-solid" as used herein refers to a
heterogeneous system in which one solid phase is dispersed in a
second liquid phase.
[0065] The pH measurements for formulations and compositions
described herein, wherein the formulations or compositions do not
comprise a predominantly aqueous environment, are more aptly
described as "apparent pH" values as the pH values are not
determined in a predominantly aqueous environment. In such cases,
the influence of, for example, organic solvents on the pH
measurement may result in a shift of pH relative to a true aqueous
environment.
[0066] The term "carrier" or "vehicle" as used herein refers to
carrier materials (other than the pharmaceutically active
ingredient) suitable for transdermal administration of a
pharmaceutically active ingredient. A vehicle may comprise, for
example, solvents, cosolvents, permeation enhancers, pH buffering
agents, antioxidants, gelling agents, additives, or the like,
wherein components of the vehicle are nontoxic and do not interact
with other components of the total composition in a deleterious
manner.
[0067] The phrase "non-occlusive, transdermal drug delivery" as
used herein refers to transdermal delivery methods or systems that
do not occlude the skin or mucosal surface from contact with the
atmosphere by structural means, for example, by use of a patch
device, a fixed application chamber or reservoir, a backing layer
(for example, a structural component of a device that provides a
device with flexibility, drape, or occlusivity), a tape or bandage,
or the like that remains on the skin or mucosal surface for a
prolonged period of time. Non-occlusive, transdermal drug delivery
includes delivery of a drug to skin or mucosal surface using a
topical medium, for example, creams, ointments, sprays, solutions,
lotions, gels, and foams. Typically, non-occlusive, transdermal
drug delivery involves application of the drug (in a topical
medium) to skin or mucosal surface, wherein the skin or mucosal
surface to which the drug is applied is left open to the
atmosphere.
[0068] The term "transdermal" delivery, as used herein refers to
both transdermal (and "percutaneous") and transmucosal
administration, that is, systemic delivery by passage of a drug
through a skin or a mucosal tissue surface and ultimately into the
bloodstream.
[0069] The term "topical" delivery, as used herein refers to local
delivery of a drug into a skin surface or a mucosal tissue surface
with minimal passage into the bloodstream.
[0070] The phrase "therapeutically effective amount" as used herein
refers to a nontoxic but sufficient amount of a drug, agent, or
compound to provide a desired therapeutic effect, for example, one
or more doses of 5-alpha-reductase inhibitor that will be effective
in relieving androgenetic alopecia, benign prostate hyperplasia, or
prostate cancer.
[0071] The term "5-alpha-reductase inhibitor" as used herein refers
to any of the conventional 5-alpha-reductase inhibitors. The
preferred 5-alpha-reductase inhibitors of the present invention are
azasteroid compounds. Even more preferred 5-alpha-reductase
inhibitors of the present invention are finasteride, dutasteride,
pharmaceutically acceptable salts thereof, pharmaceutically
acceptable derivatives thereof, as well as mixtures thereof.
[0072] The term "5-alpha-reductase inhibitor pharmaceutically
acceptable salts" as used herein refers to formation of salts with
acceptable salt formers such as, but not limited to, hydrochloride,
sulphate, tosylate, mesylate, napsylate, besylate, maleate,
phosphate, salicylate, tartrate, lactate, citrate, benzoate,
succinate, acetate, pivalate, oxalate, picrate, phthalate, and the
like.
[0073] The phrase "short-chain alcohol" as used herein refers to a
C.sub.2-C.sub.4 alcohol, for example, ethanol, propanol, butanol,
isopropanol, and/or mixtures of thereof.
[0074] The phrase "volatile solvent" refers to a solvent that
changes readily from solid or liquid to a vapor, and that
evaporates readily at normal temperatures and pressures. Examples
of volatile solvents include, but are not limited to, ethanol,
propanol, butanol, isopropanol, and/or mixtures thereof. The term
"non-volatile solvent" as used herein refers to a solvent that does
not change readily from solid or liquid to a vapor, and that does
not evaporate readily at normal temperatures and pressures.
Examples of non-volatile solvents include, but are not limited to,
propylene glycol, glycerin, liquid polyethylene glycols,
polyoxyalkylene glycols, and/or mixtures thereof. Stanislaus, et
al., (U.S. Pat. No. 4,704,406) defined "volatile solvent" as a
solvent whose vapor pressure is above 35 mm Hg when skin
temperature is 32.degree. C., and a "non-volatile" solvent as a
solvent whose vapor pressure is below 10 mm Hg at 32.degree. C.
skin temperature. Solvents used in the practice of the present
invention are typically physiologically compatible and used at
non-toxic levels.
[0075] The phrase "monoalkylether of diethylene glycol" means a
chemical having general formula
C.sub.4H.sub.10O.sub.3(C.sub.nH.sub.2n+1) wherein n=1-4. Further,
the term "glycol" encompasses a broad range of chemicals including
but not limited to propylene glycol, dipropylene glycol, butylene
glycol, and polyethyleneglycols having general formula
CH.sub.2OH(CH.sub.20H).sub.nCH.sub.2OH wherein n (number of
oxyethylene groups)=4-200.
[0076] The phrase "permeation enhancer" or "penetration enhancer"
as used herein refers to an agent that improves the rate of
transport of a pharmacologically active agent (e.g., dutasteride)
across the skin or mucosal surface. Typically a penetration
enhancer increases the permeability of skin or mucosal tissue to a
pharmacologically active agent. Penetration enhancers, for example,
increase the rate at which the pharmacologically active agent
permeates through skin and enters the bloodstream. Enhanced
permeation effected through the use of penetration enhancers can be
observed, for example, by measuring the flux of the
pharmacologically active agent across animal or human skin as
described in the Examples herein below. An "effective" amount of a
permeation enhancer as used herein means an amount that will
provide a desired increase in skin permeability to provide, for
example, the desired depth of penetration of a selected compound,
rate of administration of the compound, and amount of compound
delivered.
[0077] The phrase "contamination" or "transfer" as used herein
means the unintended presence of harmful substances in individuals
or surfaces by direct contact between individuals, between
surfaces, or between individuals and surfaces (and
reciprocally).
[0078] The phrase "synergy", "synergism", "synergistic effect" or
"synergistic action" as used herein means an effect of the
interaction of the actions of two agents such that the result of
the combined action is greater than expected as a simple additive
combination of the two agents acting separately.
[0079] The phrase "modulate", "regulate" or "control" as used
herein means to adjust, or maintain, with respect to a desired
rate, degree, or condition, as to adjust permeation rate,
crystallization speed, and repartition of an active pharmaceutical
ingredient in the layers of the skin.
[0080] The phrase "effective" or "adequate" permeation enhancer or
combination as used herein means a permeation enhancer or a
combination that will provide the desired increase in skin
permeability and correspondingly, the desired depth of penetration,
rate of administration, and amount of drug delivered.
[0081] The phrase "thermodynamic activity" of a substance means the
energy form involved in skin permeation of this substance. The
chemical potential of a substance is defined in thermodynamics as
the partial molar free energy of the substance. The difference
between the chemical potentials of a drug outside and inside the
skin is the energy source for the skin permeation process.
[0082] The phrase "stratum corneum" as used herein refers to the
outer layer of the skin. The stratum corneum typically comprises
layers of terminally differentiated keratinocytes (made primarily
of the proteinaceous material keratin) arranged in a brick and
mortar fashion wherein the mortar comprises a lipid matrix
(containing, for example, cholesterol, ceramides, and long chain
fatty acids). The stratum corneum typically creates the
rate-limiting barrier for diffusion of the active agent across the
skin.
[0083] The phrase "intradermal depot" as used herein refers to a
reservoir or deposit of a pharmaceutically active compound within
or between the layers of the skin (e.g., the epidermis, including
the stratum corneum, dermis, and associated subcutaneous fat),
whether the pharmaceutically active compound is intracellular
(e.g., within keratinocytes) or intercellular.
[0084] The term "subject" as used herein refers to any warm-blooded
animal, particularly including a member of the class Mammalia such
as, without limitation, humans and non human primates such as
chimpanzees and other apes and monkey species; farm animals such as
cattle, sheep, pigs, goats and horses; domestic mammals such as
dogs and cats; laboratory animals including rodents such as mice,
rats and guinea pigs, and the like. The term does not denote a
particular age or sex.
[0085] The term "sustained release" as used herein refers to
predetermined continuous release of a pharmaceutically active agent
to provide therapeutically effective amounts of the agent over a
prolonged period. In some embodiments of the present invention, the
sustained release occurs at least in part from an intradermal depot
of a pharmaceutically active compound.
[0086] The term "prolonged period" as used herein typically refers
to a period of at least about 12 hours, more preferably at least
about 18 hours and more preferably at least about 24 hours.
[0087] The term "sustained release dosage form" as used herein
refers to a dosage form that provides an active agent, e.g.,
dutasteride, substantially continuously for several hours,
typically for a period of at least about 12 to about 24 hours.
[0088] The term "delivery rate" as used herein refers to the
quantity of drug delivered, typically to plasma, per unit time, for
example, nanograms of drug released per hour (ng/hr) in vivo.
[0089] In the context of plasma blood concentration of active
agent, the term "C" as used herein refers to the concentration of
drug in the plasma of a subject, generally expressed as mass per
unit volume, typically nanograms per milliliter (this concentration
may be referred to as "plasma drug concentration" or "plasma
concentration" herein which is intended to be inclusive of drug
concentration measured in any appropriate body fluid or tissue).
The plasma drug concentration at any time following drug
administration is typically referred to as Ctime as in C 10h or
C20h, etc. The term "C.sub.max" refers to the maximum observed
plasma drug concentration following administration of a drug dose,
and is typically monitored after administration of a first dose
and/or after steady-state delivery of the drug is achieved. The
following terms are used herein as follows: "Cavg" refers to
average observed plasma concentration typically at steady state,
Cavg at steady state is also referred to herein as "Css"; "Cmin"
refers to minimum observed plasma concentration typically at steady
state.
[0090] The term "Tmax" as used herein refers to the time to maximum
plasma concentration and represents the time that elapses between
administration of the formulation and a maximum plasma
concentration of drug (i.e., a peak in a graph of plasma
concentration vs. time). Tmax values may be determined during an
initial time period (for example, related to administration of a
single dose of the drug) or may refer to the time period between
administration of a dosage form and the observed maximum plasma
concentration during steady state.
[0091] The term "steady state" as used herein refers to a pattern
of plasma concentration versus time following consecutive
administration of a constant dose of active agent at predetermined
intervals (for example, once-a-day dosing). During "steady state"
the plasma concentration peaks and plasma concentration troughs are
substantially the same within each dosing interval.
[0092] One of ordinary skill in the art appreciates that
intradermal concentrations or plasma drug concentrations obtained
in individual subjects will vary due to inter-subject variability
in many parameters affecting, for example, drug absorption,
distribution, metabolism, and excretion. Accordingly, mean values
obtained from groups of subjects are typically used for purposes of
comparing plasma drug concentration data and for analyzing
relationships between in vitro dosage assays and in vivo plasma
drug concentrations.
[0093] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particular
embodiments described herein, for example, particular solvent(s),
antioxidant(s), cosolvent(s), penetration enhancer(s), buffering
agent(s), and/or gelling agent(s), and the like, as use of such
particulars may be selected in view of the teachings of the present
specification by one of ordinary skill in the art. It is also to be
understood that the terminology used herein is for the purpose of
describing particular embodiments of the invention only, and is not
intended to be limiting.
[0094] In one aspect, the present invention relates to a
non-occlusive composition for pharmaceutical drug delivery. The
composition may be formulated to be suitable for systemic
application, for example, transcutaneous and/or transmucosal
applications. The composition typically comprises a therapeutically
effective amount of 5-alpha-reductase inhibitor or a
pharmaceutically acceptable salt or derivative thereof. The
composition typically comprises a primary vehicle comprising a
mixture of water, at least one short-chain alcohol, a
monoalkylether of diethylene glycol, and a glycol. The composition
may optionally comprise other inactive ingredients without
departing from the scope of the present invention. In one
embodiment, the 5-alpha-reductase inhibitor is dutasteride or
finasteride. In other embodiments, the dutasteride or finasteride
is a pharmaceutically acceptable salt or a pharmaceutically
acceptable derivative salt of finasteride or dutasteride. A
preferred concentration range of the 5-alpha-reductase inhibitor is
about 0.01 to about 5 weight percent, more preferred is a
concentration of about 0.05 to about 1 weight percent.
[0095] The short-chain alcohol in formulations of the present
invention may be, for example, ethanol, propanol, butanol,
isopropanol, and mixtures thereof. A preferred concentration range
of the short-chain alcohol, for example, ethanol, is a
concentration of about 5 to about 75 weight percent where the water
is present at a concentration of about 10 to about 60 weight
percent. Water can be added quantum sufficiat (q.s.) so amounts may
vary as can be determined by one of ordinary skill in the art in
view of the teachings of the present specification. A more
preferred concentration range of the short-chain alcohol, for
example, ethanol, is about 30 to about 70 weight percent where the
water is present at a concentration of about 10 to about 40 weight
percent.
[0096] The formulations of the present invention further comprise a
combination of a monoalkylether of diethylene glycol (for example
mono ethyl ether of diethylene glycol) and a pharmaceutically
acceptable glycol. In one embodiment the glycol is propylene
glycol. A preferred concentration range of the monoalkylether of
diethylene glycol and of the pharmaceutically acceptable glycol is
a concentration of about 1 to about 30 weight percent, more
preferred is a concentration of about 2.5 to about 20 weight
percent. More preferred formulations of the present invention
comprise combination wherein the monoalkylether of diethylene
glycol to the pharmaceutically acceptable glycol ratio ranges from
about 10:1 to 1:10, and wherein the monoalkylether of diethylene
glycol and the pharmaceutically acceptable glycol are present in
combination in a cumulative amount of not less than 15 weight
percent and not more than 60 weight percent of the total
composition.
[0097] Further, the formulations of the present invention may
further comprise a gelling or thickening agent(s). Exemplary
gelling agents include, but are not limited to, carbomer,
carboxyethylene or polyacrylic acid such as carbomer 980 or 940 NF,
981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020, 2050,
934P NF, 971P NF, 974P NF, polycarbophils such as NOVEON AA-1,
NOVEON CA1/CA2, carbomer copopolymers such as PEMULEN TR1 NF or
PEMULEN TR2 NF, carbomer interpolymers such as CARBOPOL ETD 2020
NF, CARBOPOL ETD 2050 NF, CARBOPOL ULTRA EZ 10, etc. . . . ;
cellulose derivatives such as ethylcellulose,
hydroxypropylmethylcellulose (HPMC), ethyl-hydroxyethylcellulose
(EHEC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC),
hydroxyethylcellulose (HEC), etc. . . . ; natural gums such as
arabic, xanthan, guar gums, alginates, etc. . . . ;
polyvinylpyrrolidone derivatives; polyoxyethylene polyoxypropylene
copolymers, etc; others like chitosan, polyvinyl alcohols, pectins,
veegum grades, and the like. Other suitable gelling agents to apply
the present invention include, but are not limited to, carbomers.
Alternatively, other gelling agents or viscosant known by those
skilled in the art may also be used. The gelling agent or thickener
is present from about 0.2 to about 30% w/w depending on the type of
polymer, as known by one skilled in the art. A preferred
concentration range of the gelling agent(s), for example,
hydroxypropyl cellulose or carbomer, is a concentration of between
about 0.5 and about 5 weight percent, more preferred is a
concentration of between about 1 and about 3 weight percent.
[0098] The formulations of the present invention may also further
comprise a permeation enhancer (penetration enhancer). Permeation
enhancers include, but are not limited to, sulfoxides such as
dimethylsulfoxide and decylmethylsulfoxide; surfactants such as
sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium
bromide, benzalkonium chloride, poloxamer (231, 182, 184), tween
(20, 40, 60, 80) and lecithin; the 1-substituted
azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one; fatty alcohols such as lauryl
alcohol, myristyl alcohol, oleyl alcohol and the like; fatty acids
such as lauric acid, oleic acid and valeric acid; fatty acid esters
such as isopropyl myristate, isopropyl palmitate, methylpropionate,
and ethyl oleate; polyols and esters thereof such as propylene
glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol,
and polyethylene glycol monolaurate, amides and other nitrogenous
compounds such as urea, dimethylacetamide (DMA), dimethylformamide
(DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine,
diethanolamine and triethanolamine, terpenes; alkanones, and
organic acids, particularly salicylic acid and salicylates, citric
acid and succinic acid. As noted earlier herein, "Percutaneous
Penetration Enhancers", eds. Smith et al. (CRC Press, 1995), which
is incorporated herein by reference thereto, provides an excellent
overview of the field and further information concerning possible
secondary enhancers for use in conjunction with the present
invention. More permeation enhancer(s) suitable to be used with the
present invention may be known by those skilled in the art. The
permeation enhancer is present from about 0.1 to about 30% w/w
depending on the type of compound. Preferred permeation enhancers
are fatty alcohols and fatty acids. More preferred permeation
enhancers are fatty alcohols. Preferably, the fatty alcohols have
the formula the CH.sub.3(CH.sub.2).sub.n(CH).sub.mCH.sub.2OH
wherein n ranges from (8-m) to (16-m) and m=0-2. A preferred
concentration range of the penetration enhancer(s) is, depending on
the type of permeation enhancer, a concentration of between about
0.1 and about 10 weight percent, as known by one skilled in the
art. In one preferred embodiment, the penetration enhancer
comprises myristyl alcohol in a concentration of between about 0.1
and about 2 weight percent.
[0099] A preferred concentration range of the antioxidant(s) of the
formulations of the present invention, for example, tocopherol and
derivatives, ascorbic acid and derivatives, butylated
hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid,
propyl gallate, sodium metabisulfite and derivatives, is a
concentration of about 0.01 to about 5 weight percent; more
preferred is a concentration of about 0.1 to about 0.5 weight
percent, depending on the type of antioxidant used, as known by the
one skilled in the art.
[0100] A preferred concentration range of the buffering agent(s) of
the formulations of the present invention, for example, carbonate
buffers, citrate buffers, phosphate buffers, acetate buffers,
hydrochloric acid, lactic acid, tartaric acid, inorganic and
organic bases, is a concentration of about 1 to about 10 weight
percent, more preferred is a concentration of about 2 to about 5
weight percent, depending on the type of buffering agent(s) used,
as known by the one skilled in the art. The preferred concentration
range of said buffering agents are those enabling design of
compositions having a pH close to the physiologic pH of the skin,
between about pH 4.5 and about pH 8.5, preferably between about pH
4.5 and pH 6.5, and even more preferably between pH 5.5 and pH 6.5.
Concentrations of the buffering agent(s) may vary, however, as
known by the one skilled in the art. The buffering agent may
replace up to 100% of the water amount within the composition.
[0101] The transdermal or topical pharmaceutical formulation of the
present invention may also further include preservatives such as
benzalkonium chloride and derivatives, benzoic acid, benzyl alcohol
and derivatives, bronopol, parabens, centrimide, chlorhexidine,
cresol and derivatives, imidurea, phenol, phenoxyethanol,
phenylethyl alcohol, phenylmercuric salts, thimerosal, sorbic acid
and derivatives. The preservative is present from about 0.01 to
about 10% w/w depending on the type of compound used, as known by
the one skilled in the art.
[0102] The transdermal or topical pharmaceutical formulation of the
present invention may also further include humectants, sequestering
agents, moisturizers, surfactants, emollients, colorants,
fragrances, flavors, or any combination thereof.
[0103] In one embodiment, a gel formulation of the present
invention comprises a therapeutically effective amount of a
5-alpha-reductase inhibitor, or a pharmaceutically acceptable salt
or derivative thereof, of between about 0.01 to about 5 weight
percent. The primary vehicle may comprise between about 10 to about
60 weight percent of water, between about 30 to about 70 weight
percent ethanol, between about 15 and about 60 weight percent of a
10:1 to 1:10 (weight to weight) mixture of diethylene glycol mono
ethyl ether and propylene glycol, and between about 0.1 and about 2
weight percent of lauryl alcohol, myristyl alcohol, oleyl alcohol,
lauric acid, myristic acid, or oleic acid. The primary vehicle may
be gellified with between about 0.5 and about 5 weight percent of
hydroxypropylcellulose. The apparent pH of the gel is between about
pH 4.5 and about pH 8.5, or preferably between about pH 5.5 and pH
6.5.
[0104] Preferred embodiments of the present invention are gel
formulations for non-occlusive therapeutic, transdermal or topical
applications. In such embodiments transdermal delivery methods or
systems do not occlude the skin or mucosal surface from contact
with the atmosphere by structural means, for example, there is no
backing layer used to retain the gel formulation in place on skin
or mucosal surface.
[0105] The formulations of the present invention may be provided in
a unit dose container(s). Such containers typically comprise inner
and outer surfaces, wherein the formulation of the present
invention is contained by the inner surface of the container. In
selected embodiments, the container is a packet or a vial, and the
inner surface of the container may further comprise a liner. For
example, in one embodiment, the container is a flexible, foil
packet and the liner is a polyethylene liner. Alternatively, or in
addition, the formulations of the present invention may be provided
in a multiple dose container(s). Such multiple dose containers
typically comprise inner and outer surfaces, wherein the gel for
pharmaceutical drug delivery is contained by the inner surface of
the container. Multiple dose containers may, for example, dispenses
fixed or variable metered doses. Multiple dose containers may, for
example, be a stored-energy metered dose pump or a manual metered
dose pump.
[0106] In another aspect the present invention comprises a
composition for pharmaceutical drug delivery, comprising a
therapeutically effective amount of 5-alpha-reductase inhibitor, or
a pharmaceutically acceptable salt or derivative thereof, in a
hydroalcoholic vehicle comprising water, a short chain alcohol, a
monoalkyl ether of diethylene glycol, a pharmaceutically acceptable
glycol, and an optional fatty permeation enhancer. In such
compositions the pH of the composition is typically between about
pH 4.5 and about pH 8.5. Further, the transdermal flux (for
example, instant flux) of the 5-alpha-reductase inhibitor, in the
hydroalcoholic vehicle, across skin is greater than the transdermal
flux of an equal concentration of 5-alpha-reductase inhibitor in an
alcoholic solution (that is, an anhydrous solution without the
propylene glycol, without the diethylene glycol mono ethyl ether,
without the optional fatty permeation enhancer) of essentially
equivalent pH over an essentially equivalent time period, wherein
the skin is the flux rate controlling membrane. These compositions
for pharmaceutical delivery may include further components as
described herein, for example, the hydroalcoholic vehicle may
further comprise a permeation enhancer. Such compositions may be
formulated in a variety of ways including wherein the
hydroalcoholic vehicle is gellified. These compositions may be
used, for example, for transdermal applications including
application to skin surfaces (arm, shoulder, abdomen, scalp, thigh)
and mucosal tissues (for example, intranasally, intrabucally, as a
vaginal ovule or as a suppository).
[0107] In yet another aspect the present invention comprises a
composition for pharmaceutical drug delivery, comprising a
therapeutically effective amount of 5-alpha-reductase inhibitor, or
a pharmaceutically acceptable salt or derivative thereof, in a
hydroalcoholic vehicle comprising water, a short chain alcohol, a
monoalkyl ether of diethylene glycol, a pharmaceutically acceptable
glycol, and an optional fatty permeation enhancer. These
compositions for pharmaceutical delivery may include further
components as described herein, for example, the hydroalcoholic
vehicle may further comprise a cosolvent(s), a penetration
enhancer(s), a buffering agent(s), a preservative(s), an
emollient(s), an humectant(s), and/or a gelling agent(s). Such
compositions may be formulated in a variety of ways including
wherein the hydroalcoholic vehicle is gellified. These compositions
may be used, for example, for transdermal applications including
application to skin surfaces (arm, shoulder, abdomen, scalp, thigh)
and mucosal tissues (for example, intranasally, intrabucally, as a
vaginal ovule or as a suppository).
[0108] In a further aspect, the present invention includes methods
of manufacturing the compositions described herein for
pharmaceutical drug delivery. In one embodiment, the method of
manufacturing comprises mixing the components to yield a
homogeneous gel, wherein the pH of the gel is between about pH 4.5
and about pH 8.5 (exemplary components include, but are not limited
to the following: a therapeutically effective amount of
5-alpha-reductase inhibitor, or a pharmaceutically acceptable salt
or derivative thereof, a primary vehicle comprising water, at least
one short-chain alcohol, a monoalkyl ether of diethylene glycol, a
pharmaceutically acceptable glycol, an optional fatty permeation
enhancer). These methods may include addition of further components
as described herein, for example, the hydroalcoholic vehicle may
further comprise cosolvent(s), penetration enhancer(s), buffering
agent(s), preservative(s), emollient(s), humectant(s), and/or
gelling agent(s). The method provides a gel suitable for
pharmaceutical systemic or intradermal delivery of
5-alpha-reductase inhibitor. Further, a method of manufacturing may
further include dispensing the pharmaceutical composition into one
or more containers (for example, a unit dose container (e.g., a
flexible, foil packet, further comprising a liner) or a multiple
dose container).
[0109] In another aspect, the present invention includes methods
for administering 5-alpha-reductase inhibitors to a human subject
in need thereof. For example, the method may comprise providing a
composition of the present invention for transdermal or topical
pharmaceutical delivery of 5-alpha-reductase inhibitors. Doses of
the compositions of the present invention may, for example, be a
gel applied to the surface of skin (arm, shoulder, thigh, abdomen,
scalp). Further, doses of the compositions of the present invention
may be applied in a single or in divided doses. In one embodiment,
the composition is applied as one or more daily dose of the gel to
a skin surface of the subject in an amount sufficient for the
5-alpha-reductase inhibitor to achieve therapeutic concentration in
the bloodstream or in the dermis of the subject, wherein up to
about 5 grams of the gel is applied daily to a skin surface area of
between about 10 to about 1000 cm.sup.2. 5-alpha-reductase
inhibitors, and pharmaceutical salts or derivatives thereof, can be
used for the treatment of a variety of conditions including benign
prostate hyperplasia, prostate cancer, and androgenetic
alopecia.
[0110] From the foregoing, it is apparent that the invention
provides a non-occlusive dosage form with a profile that permits
once daily dosing of 5-alpha-reductase inhibitors.
[0111] Further, although preferred dosage forms are described
herein, further dosage forms of the compositions of the present
invention can be determined by one of ordinary skill in the art in
view of the teachings presented herein.
[0112] Exemplary methods of making or manufacturing the
compositions of the present invention are described herein below in
the Materials and Methods section. Variations on the methods of
making the compositions of the present invention will be clear to
one of ordinary skill in the art in view of the teachings contained
herein.
[0113] The manufacturing process for formulations of the present
invention is straightforward and is typically carried out in a
closed container with appropriate mixing equipment. For example,
ethanol, propylene glycol, diethylene glycol mono ethyl ether are
mixed in a primary container (reaction vessel) under a slight
vacuum and nitrogen blanketing until a clear solution forms. In
parallel, a water-soluble 5-alpha-reductase inhibitor is dissolved
in a portion of water in a separate container and then added to the
primary solution to prepare a hydro-alcoholic solution. On the
contrary, organo-soluble 5-alpha-reductase inhibitors are dissolved
in the primary solution. The pH is then brought to its desired
value (e.g., approximately pH 5.5 to 6.5) by adding a fixed amount
of buffering agent, if required The solution may be gellified by
addition of hydroxypropylcellulose and is then stirred until the
hydroxypropylcellulose is completely swollen.
[0114] The compositions of the present invention may be applied to
a skin surface or a mucosal membrane using a variety of means,
including, but not limited to a pump-pack, a brush, a swab, a
finger, a hand, or other applicator.
[0115] The methods of manufacturing of the present invention may
include dispensing compositions of the present invention into
appropriate containers. The compositions of the present invention
may be packaged, for example, in unit dose or multi-dose
containers. The container typically defines an inner surface that
contains the composition. Any suitable container may be used. The
inner surface of the container may further comprise a liner or be
treated to protect the container surface and/or to protect the
composition from adverse affects that may arise from the
composition being in contact with the inner surface of the
container. Exemplary liners or coating materials include, but are
not limited to high density polyethylene, low density polyethylene,
very low density polyethylene, polyethylene copolymers,
thermoplastic elastomers, silicon elastomers, polyurethane,
polypropylene, polyethylene terephthalate, nylon, flexible
polyvinylchloride, natural rubber, synthetic rubber, and
combinations thereof. Liners or coating material are typically
substantially impermeable to the composition and typically to the
individual components of the composition.
[0116] A number of types of containers are known in the art, for
example, packets with rupturable barriers (see, for example, U.S.
Pat. Nos. 3,913,789, 4,759,472, 4,872,556, 4,890,744, 5,131,760,
and 6,379,069), single-use packets (see, for example, U.S. Pat.
Nos. 6,228,375, and 6,360,916), tortuous path seals (see, for
example, U.S. Pat. Nos. 2,707,581, 4,491,245, 5,018,646, and
5,839,609), and various sealing valves (see, for example, U.S. Pat.
Nos. 3,184,121, 3,278,085, 3,635,376, 4,328,912, 5,529,224, and
6,244,468). One example of a unit dose container is a flexible,
foil packet with a polyethylene liner.
[0117] Containers/delivery systems for the compositions of the
present invention may also include a multi-dose container
providing, for example a fixed or variable metered dose
application. Multi-dose containers include, but are not limited to,
a metered dose aerosol, a stored-energy metered dose pump, or a
manual metered dose pump. In preferred embodiments, the
container/delivery system is used to deliver metered doses of the
compositions of the present invention for application to the skin
of a subject. Metered dose containers may comprise, for example, an
actuator nozzle that accurately controls the amount and/or
uniformity of the dose applied. The delivery system may be
propelled by, for example, a pump pack or by use of propellants
(e.g., hydrocarbons, hydro fluorocarbons, nitrogen, nitrous oxide,
or carbon dioxide). Preferred propellants include those of the
hydrofluorocarbon (e.g., hydrofluoroalkanes) family, which are
considered more environmentally friendly than the
chlorofluorocarbons. Exemplary hydrofluoroalkanes include, but are
not limited to, 1,1,1,2-tetrafluoroethane (HFC-134(a)),
1,1,1,2,3,3,3,-heptafluoropropane (HFC-227), difluoromethane
(HFC-32), 1,1,1-trifluoroethane (HFC-143(a)),
1,1,2,2-tetrafluoroethane (HFC-134), 1,1-difluoroethane (HFC-152a),
as well as combinations thereof. Particularly preferred are
1,1,1,2-tetrafluoroethane (HFC-134(a)),
1,1,1,2,3,3,3,-heptafluoropropane (HFC-227), and combinations
thereof. Many pharmaceutically acceptable propellants have been
previously described and may be used in the practice of the present
invention in view of the teachings presented herein. The delivery
system should provide dose uniformity. In a preferred embodiment,
airless packaging with excellent barrier properties is used to
prevent degradation of 5-alpha-reductase inhibitors, for example,
airless metered-dose pumps wherein the composition comprising
5-alpha-reductase inhibitors is packaged in collapsible aluminum
foils. Accurate dosing from such pumps ensures reproducibility of
dose.
[0118] The present invention further includes methods for
administering a composition of the present invention to a subject
in need thereof. Compositions of the present invention comprising
5-alpha-reductase inhibitors can be employed, for example, for the
treatment of a variety of conditions and/or disease states which
have been historically treated by oral doses of 5-alpha-reductase
inhibitors.
[0119] The 5-alpha-reductase inhibitors compositions of the present
invention may be self-applied by a subject in need of treatment or
the composition may be applied by a care-giver or health care
professional.
[0120] The following examples are illustrative of embodiments of
the present invention and should not be interpreted as limiting the
scope of the invention.
EXPERIMENTAL
[0121] The following examples are put forth so as to provide those
of ordinary skill in the art with a complete disclosure and
description of how to make and use the formulations, methods, and
devices of the present invention, and are not intended to limit the
scope of what the inventors regard as the invention. Efforts have
been made to ensure accuracy with respect to numbers used (e.g.,
amounts, temperature, etc.) but some experimental errors and
deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, molecular weight is weight average
molecular weight, temperature is in degrees Centigrade, and
pressure is at or near atmospheric.
[0122] Materials and Methods
[0123] A. Pharmaceuticals and Reagents.
[0124] The pharmaceuticals and reagents used in the following
examples meet the strict specifications for content and purity
required for pharmaceutical products.
[0125] B. In Vitro Skin Permeation Methodology.
[0126] The in vitro human cadaver skin model has proven to be a
valuable tool for the study of percutaneous absorption and the
determination of topically applied drugs. The model uses human
cadaver skin mounted in specially designed diffusion cells that
allow the skin to be maintained at a temperature and humidity that
match typical in vivo conditions (Franz, T. J., "Percutaneous
absorption: on the relevance of in vitro data," J. Invest Dermatol
64:190-195 (1975)). A finite dose (for example: 4-7 mg/cm.sup.2) of
formulation is applied to the outer surface of the skin and drug
absorption is measured by monitoring its rate of appearance in the
receptor solution bathing the inner surface of the skin. Data
defining total absorption, rate of absorption, as well as skin
content can be accurately determined in this model. The method has
historic precedent for accurately predicting in vivo percutaneous
absorption kinetics (Franz, T. J., "The finite dose technique as a
valid in vitro model for the study of percutaneous absorption in
man," In: Skin: Drug Application and Evaluation of Environmental
Hazards, Current Problems in Dermatology, vol. 7, G. Simon, Z.
Paster, M Klingberg, M. Kaye (Eds), Basel, Switzerland, S. Karger,
pages 58-68 (1978)).
[0127] Pig skin has been found to have similar morphological and
functional characteristics as human skin (Simon, G. A., et al.,
"The pig as an experimental animal model of percutaneous permeation
in man," Skin Pharmacol. Appl. Skin Physiol. 13(5):229-34 (2000)),
as well as close permeability character to human skin (Andega, S.,
et al., "Comparison of the effect of fatty alcohols on the
permeation of melatonin between porcine and human skin," J. Control
Release 77(1-2):17-25 (2001); Singh, S., et al., "In vitro
permeability and binding of hydrocarbons in pig ear and human
abdominal skin," Drug Chem. Toxicol. 25(1):83-92 (2002); Schmook,
F. P., et al., "Comparison of human skin or epidermis models with
human and animal skin in in vitro percutaneous absorption," Int. J.
Pharm. 215(1-2):51-6 (2001)). Accordingly, pig skin may be used for
preliminary development studies and human skin used for final
permeation studies. Pig skin can be prepared essentially as
described below for human skin.
[0128] (i) Skin Preparation.
[0129] (ii) Dosing and Sample Collection.
[0130] (a) Franz cell.
[0131] (b) Automatic Sampling
[0132] (iii) Analytical Quantification Methods.
[0133] (iv) Data Analysis.
[0134] C. Formulation of Pharmaceutical Compositions.
[0135] Experiments performed in support of the present invention
showed that the order of addition of the components was not
significant, that is, the components may be added in essentially
any order during manufacturing processes. Further, nitrogen
sparging is not required during manufacturing of the pharmaceutical
compositions of the present invention but use of nitrogen sparging
or any other inert gas sparging e.g., argon sparging, is also not
counter-indicated. In the pharmaceutical formulations described
herein below, the solubility of the 5-alpha-reductase inhibitor was
not an issue.
[0136] Following here is an exemplary description of the
manufacturing process used to make the pharmaceutical compositions
of the present invention. Generally, the organic solution was
prepared, comprising, for example, solvent/cosolvent (e.g.,
ethanol/water/diethylene glycol mono ethyl ether/propylene glycol),
penetration enhancer, and thickening (or gelling) agent. The
organic solution was mixed (e.g., using mechanical mixing) to yield
a homogeneous, clear solution. The 5-alpha-reductase inhibitor was
then added to the solution and the solution mixed to obtain a
homogeneous, clear active organic solution. Water was then added
quantum sufficiat (q.s.). If desired, the pH was then adjusted to a
specified pH. In some cases, water was added and pH was adjusted
before the addition of dutasteride so that the 5-alpha-reductase
inhibitor was not exposed to high local pH variations; although
timing of the pH adjustment was not an issue. Some compositions
were purged of air by nitrogen bubbling before the
5-alpha-reductase inhibitor was dissolved; however, as noted above,
such nitrogen or argon sparging was not required. As noted above,
the components may be added in essentially any order during
manufacturing processes.
[0137] One exemplary method of manufacturing is as follows. The
organo-soluble 5-alpha-reductase inhibitor is dissolved in ethanol,
propylene glycol, diethylene glycol mono ethyl ether and myristyl
alcohol. The organic solution is mixed until homogenized using
mechanical mixing (e.g., magnetic stirring). The resulting organic
solution was clear and homogeneous. Water is added to the
5-alpha-reductase inhibitor organic solution prepared and mixed
until the solution was homogenized. Then the resulting clear and
homogeneous hydro-alcoholic solution may be further gellified by
means of cellulose derivatives thoroughly selected by the man
skilled in the art of formulating pharmaceutical topical
products.
[0138] The examples herein below exemplifies a variety of
compositions that can be prepared thanks to this manufacturing
process.
ABBREVIATIONS
[0139] DUT: Dutasteride
[0140] FIN: Finasteride
[0141] EtOH: Ethanol
[0142] IsOH Isopropanol
[0143] PG: Propylene glycol
[0144] TC: Diethylene glycol mono ethyl ether
[0145] LA: Lauryl alcohol
[0146] MA: Myristyl alcohol
[0147] OA: Oleyl alcohol
[0148] LAc: Laurie acid
[0149] MAc: Myristic acid
[0150] OAc: Oleic acid
[0151] CEL: cellulose
[0152] CAR: carbomer
[0153] TEA: Triethanolamine
[0154] DIPA: Diisopropylamine
[0155] QS: quantum sufficiat
[0156] Percentages are expressed as percent weight by weight
(w/w).
Example 1
[0157] DUT 0.05%, PG 15%, TC 15%, EtOH 50%, HCL 0.01M 0.25%, Water
QS.
Example 2
[0158] DUT 0.05%, PG 25%, TC 5%, EtOH 50%, HCL 0.00M 0.25%, Water
QS.
Example 3
[0159] DUT 0.05%, PG 5%, TC 25%, EtOH 50%, HCL 0.01M 0.25%, Water
QS.
Example 4
[0160] DUT 0.05%, PG 15%, TC 15%, EtOH 50%, CAR 1.00%, TEA 0.20%,
Water QS.
Example 5
[0161] DUT 0.5%, PG 15%, TC 15%, EtOH 50%, Water QS.
Example 6
[0162] DUT 0.5%, PG 15%, TC 15%, EtOH 50%, LAc 1%, Water QS.
Example 7
[0163] DUT 0.5%, PG 15%, TC 15%, EtOH 50%, MAc 1%, Water QS.
Example 8
[0164] DUT 0.5%, PG 15%, TC 15%, EtOH 50%, OAc 1%, Water QS.
Example 9
[0165] DUT 0.1%, PG 15%, TC 15%, EtOH 50%, MA 0.2%, CAR 1.00%, TEA
0.20%, Water QS.
Example 10
[0166] DUT 0.1%, PG 15%, TC 15%, EtOH 50%, MA 1%, CAR 1.00%, TEA
0.20%, Water QS.
Example 11
[0167] DUT 0.1%, PG 15%, TC 15%, EtOH 50%, MA 2%, CAR 1.00%, TEA
0.20%, Water QS.
Example 12
[0168] DUT 0.05%, PG 15%, TC 15%, EtOH 40%, MA 1%, CAR 1.00%, TEA
0.20%, Water QS.
Example 13
[0169] DUT 0.025%, PG 15%, TC 15%, EtOH 30%, MA 1%, CAR 1.00%, DIPA
0.20%, Water QS.
Example 14
[0170] DUT 1.0%, PG 5%, TC 10%, EtOH 70%, MA 2%, Water QS.
Example 15
[0171] FIN 0.8%, PG 5%, TC 5%, EtOH 70%, MA 0.5%, Water QS.
[0172] Examples 1-15 are illustrations of preferred formulations
according to the invention.
* * * * *