FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10, rule 13)
“IMPROVED TOPICAL MACROLIDE PHARMACEUTICAL OINTMENT FORMULATIONS”
Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai- 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE
MANNER IN WHICH IT IS TO BE PERFORMED

BACKGROUND OF THE INVENTION
1. Technical Field
[0001] The present invention relates generally to topical macrolide ointment pharmaceutical formulations.
2. Description of the Related Art
[0002] The administration of drugs and other biological materials to the bloodstream via
a transdermal route or to the localized site of action has received much attention in recent years. The skin of an average adult covers generally more than two square meters of surface area and receives about one third of all blood circulating through the body. It is elastic, rugged, and generally self generating. The skin consists of three layers: the stratum corneum, the epidermis, and the dermis.
[0003] The stratum corneum represents the rate limiting step in diffusion of chemicals
through the skin. The stratum corneum is composed of dead, keratinized, metabolically inactive
cells, which are closely packed together, and consists of an amorphous matrix of mainly lipoid
and non fibrous protein within which keratin filaments are distributed. The cells of the stratum
corneum generally contain about 20% water, while the cells below, in the stratum germinivatum
contain about 70% water. The stratum corneum does not become hydrated readily. Thus,
transdermal permeation is primarily controlled by diffusion through the stratum corneum.
[0004] Due to availability of large surface area, easy accessibility, application dynamics
and the noninvasive nature of the therapy, topical administration of drugs has long been considered a promising route of drug delivery whether the bioavailability desired is systemic, dermal, regional or localized. The topical mode of drug delivery provides many advantages over customarily used routes of administration. First, it bypasses the portal circulation and thereby the hepatic first pass metabolism. Second, topical delivery avoids the problems of variable systemic absorption and metabolism. Third, it potentially reduces gastrointestinal irritation associated with oral administration. Further, it avoids the risks and patient noncompliance associated with parenteral treatment.
[0005] The topical delivery route offers continuity of drug administration, permits use of
therapeutic agents with short biological half lives, provides treatment of cutaneous
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manifestations of diseases usually treated systemically delivers medication directly into the
systemic circulation and fosters ease of use and total patient compliance.
[0006] Ointments are semisolid preparations intended for external application to the skin
or mucous membranes. Ointments may be medicated or non-medicated. Non-medicated
ointments are ordinarily used for the physical effects that they provide as protectants, emollients
or lubricants. Medicated ointments include an active pharmaceutical ingredient (API).
Ointments include an ointment base.
[0007] Several pharmaceutical compositions are described in the literature for topical
application of macrolide related immunosuppressant drugs which are known to exhibit efficacy
in the treatment of autoimmune related skin conditions.
[0008] One example is Protopic® (tacrolimus) ointment which contains tacrolimus, a
macrolide immunosuppressant produced by Streptomyces tsukubaensis. It is typically utilized
for topical dermatologic use only. Chemically, tacrolimus is designated as [3S-
[3R*[E(lS*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*)19S*,26aR*]]-
5,6,8,1 l,12,13,14)15,16,17,18,I9,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-
3-methoxycyclohexyl)-l -methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-
propenyl)-15,19-epoxy-3H-pyrido[2,l-c][l,4] oxaazacyclotricosine-1,7,20,2 l(4H,23H)-tetrone,
monohydrate as shown in Fieure I:

Tacrolimus has an empirical formula of C44H69O12•H2O and a formula weight of 822.03. It has been demonstrated that tacrolimus inhibits T lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FK.BP-12, calcium, calmodulin, and
3

33. The process of claim 32, wherein the polyols are selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, hexylene glycol, propylene glycol monocaprylate and mixtures thereof.
34. The process of claim 26, comprising dissolving about 0.01 to about 5 % w/w of the macrolide related immunosuppressant in about 0.01 to about 30 % w/w of the skin penetration enhancer.
35. A method for delivering a macrolide related immunosuppressant through the skin in order to treat conditions situated on and beneath the skin is provided, the method comprising the step of topically administering an effective amount of a pharmaceutical ointment composition comprising (a) a therapeutically effective amount of one or more active pharmaceutical ingredient comprising one or more macrolide related immunosuppressants or pharmaceutically acceptable salts or esters thereof; (b) an ointment base; and (c) one or more skin penetration enhancers capable of percutaneous delivery of the macrolide related immunosuppressant through the skin.
36. The method of claim 35, wherein the macrolide related immunosuppressant is selected from the group consisting of tacrolimus, pimecrolimus, sirolimus, acsomycin, everolimus, pharmaceutically acceptable salts or esters thereof and mixtures thereof.
37. The method of claim 35, wherein the pharmaceutical ointment composition comprises about 0.01 to about 5 % w/w of the macrolide related immunosuppressant and about 0.01 to about 30 % w/w of the skin penetration enhancer.
38. The method of claim 35, wherein the pharmaceutical ointment composition comprises about 0.02 to about 2 % w/w of the macrolide related immunosuppressant and about 1 to about 10 % w/w of the skin penetration enhancer.
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calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This effect has been shown to prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-a, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to down regulate the expression of FceRI on Langerhans cells.
[0010] Tacrolimus is indicated for short-term and intermittent long-term therapy in the
treatment of patients with moderate to severe atopic dermatitis in whom the use of alternative,
conventional therapies are deemed inadvisable because of potential risks, or in the treatment of
patients who are not adequately responsive to or are intolerant of alternative, conventional
therapies. See, e.g., Physician's Desk Reference, "Protopic," 58th Edition, p. 1327-1330 (2003).
[0011] Another example is Elidel® (pimecrolimus) Cream 1% which contains the
compound pimecrolimus, the 33-epi-chloro-derivative of the macrolactam ascomycin. Chemically, pimecrolimus is (lR>9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(lE)-2-{(lR,3R,4S)-4-chloro-3-methoxycyclohexyl}-l-methylvinyl]-17-ethyl-l,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone as shown in Figure II:

Pimecrolimus has the empirical formula C43H68CINO11 and a molecular weight of 810.47. Pimecrolimus has been demonstrated to bind with high affinity to macrophilin-12 (FKBP-12)
4

and inhibit the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T-cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Thl-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T cells. In addition, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/IgE. Pimecrolimus is indicated for short-term and intermittent long-term therapy in the treatment of mild to moderate atopic dermatitis. See, e.g., Physician's Desk Reference, "Elide!," 58th Edition, p. 2250-2252 (2003).
[0012] Yet another example is Rapamune® (sirolimus) which is an immunosuppressive
agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as rapamycin) is (3Sf6Rs7E,9Rf10RJ12R,14S,15El17E,19E,21S,23S,26R,27RJ4aS)-
9,10,12,13,14,21J22,23,24,25l26,2732,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(lR)-2-[(lS,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-l-methylethyl]-10,21-dimethoxy-6,8,12,14,20, 26-hexamethyl-23,27-epoxy-3H-pyrido[2,l-c][l,4]oxaazacyclohentriacontine-l,5,ll,28,29(4H, 6H,31H)-pentone as shown in Figure III:

Sirolimus has a molecular formula of C51H79NO13 and its molecular weight is 914.2. Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an
5

immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the Gl to the S phase of the cell cycle. Sirolimus is indicated for the prophylaxis of organ rejection in patients receiving renal transplants. See, e.g., Physician's Desk Reference, "Rapamune," 58th Edition, p. 3483-3490 (2003).
SUMMARY OF THE INVENTION
[0013] In accordance with one embodiment of the present invention, a pharmaceutical
ointment composition is provided comprising (a) a therapeutically effective amount of one or more active pharmaceutical ingredient comprising one or more macrolide related immunosuppressants or pharmaceutically acceptable salts or esters thereof; (b) an ointment base; and (c) one or more skin penetration enhancers capable of percutaneous delivery of the macrolide related immunosuppressant through the skin,
[0014] In accordance with a second embodiment of the present invention, a process for
preparing a macrolide related immunosuppressant ointment pharmaceutical composition is
provided comprising (a) dissolving a therapeutically effective amount of one or more active
pharmaceutical ingredient comprising one or more macrolide related immunosuppressants or
pharmaceutically acceptable salts or esters thereof in one or more penetration enhancers; (b)
providing an ointment base; and (c) mixing the product of step (a) with the product of step (b).
[0015] In accordance with a third embodiment of the present invention, a method for
delivering a macrolide related immunosuppressant through the skin in order to treat conditions situated on and beneath the skin is provided, the method comprising the step of topically administering an effective amount of a pharmaceutical ointment composition comprising (a) a therapeutically effective amount of one or more active pharmaceutical ingredient comprising one or more macrolide related immunosuppressants or pharmaceutically acceptable salts or esters thereof; (b) an ointment base; and (c) one or more skin penetration enhancers capable of percutaneous delivery of the macrolide related immunosuppressant through the skin.
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DEFINITIONS
[0016] The term "treating" or "treatment" of a state, disorder or condition as used herein
means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
[0017] The term "therapeutically effective amount" as used herein means the amount of a
compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
[0018] The term "delivering" as used herein means providing a therapeutically effective
amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host.
[0019] By "pharmaceutically acceptable" is meant those salts and esters which are,
within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, lauryl sulphate salts and the like. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts, and the like.
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[0020] The term "subject" or "a patient" or "a host" as used herein refers to mammalian
animals, preferably human.
[0021] As used herein the term "antioxidant" is intended to mean an agent who inhibits
oxidation and is thus used to prevent the deterioration of preparations by the oxidative process. Such compounds include, by way of example and without limitation, ascorbic acid, ascorbic palmitate, Vitamin E, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metalbisulfite and other such materials known to those of ordinary skill in the art.
[0022] As used herein, the term "buffering agent" is intended to mean a compound used
to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dehydrate and other such material known to those of ordinary skill in the art.
[0023] As used herein, the term "binders" is intended to mean substances used to cause
adhesion of powder particles in tablet granulations. Such compounds include, by way of example and without limitation, acacia alginic acid, tragacanth, carboxymethylcellulose sodium, poly (vinylpyrrolidone), compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch, combinations thereof and other material known to those of ordinary skill in the art.
[0024] When needed, other binders may also be included in the present invention.
Exemplary binders include starch, poly(ethylene glycol), guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers (PLURONIC™ F68, PLURONIC™ f!27), collagen, albumin, celluloses in nonaqueous solvents, combinations thereof and the like. Other binders include, for example, poly(propylene glycol), polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, poly(ethylene oxide), microcrystalline cellulose, poly(vinylpyrrolidone), combinations thereof and other such materials known to those of ordinary skill in the art.
[0025] As used herein, the term "wetting agent" is intended to mean a compound used to
aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents
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include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum
acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol
monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,
polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000),
polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, (e.g.,
TWEEN™s), polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide,
phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose
sodium, methylcellulose, hydroxyethylcellulose, hydroxyl propylcellulose,
hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Tyloxapol (a nonionic liquid polymer of the alkyl aryl polyether alcohol type, also known as superinone or triton) is another useful wetting agent, combinations thereof and other such materials known to those of ordinary skill in the art.
[0026] Most of the excipients herein are described in detail in, for example, Howard C.
Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, (7th Ed. 1999); Alfonso R. Gennaro et al., Remington: The Science and Practice of Pharmacy, (20th Ed. 2000); and A. Kibbe, Handbook of Pharmaceutical Excipients, (3rd Ed. 2000), which are incorporated by reference herein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] One aspect of the present invention provides a pharmaceutical ointment
composition containing at least (a) a therapeutically effective amount of one or more active pharmaceutical ingredient comprising one or more macrolide related immunosuppressants or pharmaceutically acceptable salts or esters thereof; (b) an ointment base; and (c) one or more skin penetration enhancers capable of percutaneous delivery of the macrolide related immunosuppressant through the skin. The macrolide related immunosuppressants for use herein can be any known macrolide immunosuppressants and includes, but are not limited to, tacrolimus, pimecrolimus, sirolimus, acsomycin, everolimus, pharmaceutically acceptable salts thereof and the like and mixtures thereof.
9

[0028] The ointment may be any commonly known commercially available ointments.
As one skilled in the art will readily appreciate, the specific ointment base to be used is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. Generally, the ointment base may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. See, e.g., Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa.: Mack Publishing Co., pp. 1301-1306 (1985). Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, semisolid hydrocarbons obtained from petroleum and the like. Examples of oleaginous ointment bases include white ointment, yellow ointment, cetyl esters wax, paraffin, petrolatum, white petrolatum, white wax, yellow wax and the like and mixtures thereof. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxy stearin sulfate, anhydrous lanolin, hydrophilic petrolatum and the like and mixtures thereof. Emulsion ointment bases are either water-in-oil (W/O) emulsions, e.g. hydrophilic petrolatum, or oil-in-water (O/W) emulsions, and can include, for example, cetyl alcohol, lanolin, glyceryl monostearate, stearic acid and the like and mixtures thereof. Useful water-soluble ointment bases can be those prepared from glycol ethers such as, for example, polyethylene glycols of varying molecular weight, polysorbates and the like and mixtures thereof.
[00291 "Penetration enhancement" or "permeation enhancement" as used herein relates to
an increase in the permeability of the skin or mucosal tissue to the selected pharmacologically active agent, which in turn gives rise to an increase in the rate at which the drug permeates into and/or through the skin or mucosal tissue. Accordingly, the skin penetration enhancers herein are employed to improve the permeability of an active pharmaceutical ingredient through the skin. Exemplary penetration enhancers include, by way of example and without limitation, volatile organic solvents (e.g. alcohols such as ethanol), nonvolatile organic solvents (e.g. amides such as pyrrolidones; polyol ethers such as glycol ethers; polyols such as glycols; and derivatives thereof) and mixtures thereof.
[0030] Suitable volatile organic solvents include, but are not limited to, aliphatic,
cycloaliphatic and/or aromatic-aliphatic alcohols, each of which is monohydric or polyhydric,
10

alcohol/water mixtures, saturated and/or unsaturated fatty alcohols which each contain from
about 8 to about 18 carbon atoms, saturated and/or unsaturated fatty acids which each from about
8 to about 18 carbon atoms and/or esters thereof and the like and mixtures thereof. Useful
alcohols are those having from 1 to about 20 carbon atoms, e.g., ethanol, isopropyl alcohol.
Topical ethanol solutions are used as penetration enhancers at a concentration ranging from
about 1% v/v to about 90% v/v. See, e.g., A. Kibbe, Handbook of Pharmaceutical Excipients,
3rd Ed. (2000). In the formulation of hydro alcoholic gels, the amounts of ethanol may vary
greatly, even outside the ranges given by the Handbook of Pharmaceutical Excipients. In the
present invention, alcohol can be used as co-solvent cum penetration enhancer for the API.
While not being bound to any particular theory, there are two theories supporting the use of
alcohol as skin penetration enhancer. First, the alcohol evaporates fast and concentrates the drug
in the residual formulation that remains on the skin. It is hypothesized that some thermodynamic
activity will drive the drug into the stratum corneum. Second, the alcohol alters the physical
integrity of the stratum corneum barrier resulting in an increase in the ability of the drug to
penetrate the skin. Commercially, denatured alcohol such as SDA 40 is often used in place of
Alcohol USP (ethanol), and it may be used here also. While ethanol is the preferred alcohol,
isopropyl alcohol and other pharmaceutically acceptable alcohols may be used in this invention.
[0031] Useful amides for use a nonvolatile organic solvents include, but are not limited
to, N,N-dimethyl acetamide (DMA) N,N-diethyl toluamide, N,N-dimethyl formamide, N,N-dimethyl octamide, N,N-dimethyl decamide, and the like; pyrrolidone derivatives such as N-alkylpyrrolidones (e.g., N-methyl-2-pyrrolidones), vinyl pyrrolidone, 2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, N-(2-hydroxyethyl)-2-pyrrolidone or fatty acid esters thereof, 1-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-tallowalkylpyrrolidones, and the like and mixtures thereof. The present invention preferably employs N-methyl-2-pyrrolidone as a nonvolatile type of penetration enhancer. N-methyl-2-pyrrolidone is commercially available as Pharmasolve (available from ISP Corp. of Wayne, New Jersey), a safe and compatible material. Generally, Pharmasolve® increases the water solubility of insoluble drugs and can therefore develop insoluble drugs into topical products.
[0032] Solubility enhancement can be attributed to three parameters: nonpolar molecular
dispersion, polar type chemical bonding and hydrogen bonding. N-methyl-2-pyrrolidone can
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undergo a large number of chemical reactions at various positions on the pyrrolidone ring. The enhanced solubility can be attributed to a complexing action with the nitrogen and carbonyl reactive centers of the molecule. A preferred N-methyl-2-pyrrolidone is Pharmasolve® which is a drug solubilizer and therefore enhances the bioavailability of topical formulations. It can increase the solubility of many drugs that are not water-soluble thereby enhancing their physico-chemical stability and bioavailability.
[0033] Pharmasolve's® favorable safety profile makes it a solubilizer of choice for use in
pharmaceutical formulations. Furthermore, in contrast to other drug solubilizing agents, Pharmasolve has a favorable toxicity profile, making it a suitable candidate for use in a variety of topical dosage forms. Pharmasolve® is practically nonirritating to rabbit skin. (PII=0.5). According to the manufacturer's brochure, when Pharmasolve® was analyzed in a repeated insult patch test using 50 human subjects and a total of 15 applications, N-methyl-2-pyrrolidone was neither a primary dermal irritant nor a sensitizer.
[0034] Polyol ethers for use herein can C2-C30 polyol ethers containing from 2 to about
10 hydroxyl groups. Representative of the polyol ethers are glycol ethers which include, by way of example and without limitation, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol monopropyl ether, ethylene glycol monophenyl ether, ethylene glycol monohexyl ether, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, triethylene glycol monobutyl ether, ethylene glycol monohexyl ether, diethyl glycol monohexyl ether, ethylene glycol phenyl ether. Glycols include, by way of example and without limitation, butylene glycol, propylene glycol, polypropylene glycol, polyethylene glycol, hexylene glycol, polyethylene glycol dodecyl ether, diethylene glycol monoethyl ether, polyethylene glycol-8-glyceryl caprylate, propylene glycol monocaprylate and the like and mixtures thereof.
[0035] Diethylene glycol monoethyl ether, commercially available as Transcutol®
(available from Gattefosse of St Priest Mi-Plaine, France). Transcutol® can solubilize hydrophobic materials. The increased drug flux across the stratum corneum is explained by the diffusion of Transcutol® into it, thereby changing the ability of the drug to penetrate the
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intercellular space. It is believed that the primary role of Transcutol is the modification of the
thermodynamic activity of the drug. By direct action on its solubility, Transcutol® favors the
passage of larger quantities of the drug into the stratum corneum allowing a greater solubilization
in the aqueous domains of the tissue. Currently, there are various clinical studies conducted in
the U.S. using Transcutol® in topical products (Phase I, II and III clinical trials)
[0036] Polyols for use herein can be C2-C30 polyols containing from 2 to about 10
hydroxyl groups. Suitable polyols according to the present invention include, but are not limited
to, ethylene glycol, propylene glycol, butylene glycol, hexylene glycol, propylene glycol
monocaprylate and mixtures thereof. Propylene glycol is widely used as a solvent or a co-
solvent in topicals ranging from about 1% to about 90%. It is also used as a humectant in an
amount of about 15%. See, e.g., A. Kibbe, Handbook of Pharmaceutical Excipients, 3rd Ed.
(2000). In hydro alcoholic gel formulations, alcohol evaporates, propylene glycol and water
forms a saturated solution of drug, which enhances flux of drug across the skin.
[0037] Generally, the amount of the active pharmaceutical ingredient present in the
topical pharmaceutical compositions of the present invention can range from about 0.01 to about 5 % w/w and preferably from about 0.02 to about 2 %w/w. The penetration enhancer will ordinarily be present in an amount sufficient to enhance the penetration of the macrolide related immunosuppressant into the skin. The specific amount varies necessarily according to the desired release rate and specific form of the macrolide related immunosuppressant used. Generally, this amount is in the range of about 0.01 to about 30 % w/w and preferably from about 1 to about 10 % w/w to be administered to a patient.
[0038] If desired, the topical pharmaceutical compositions of the present invention can
contain additional active pharmaceutical ingredients depending on the particular condition being treated. Examples of additional active pharmaceutical ingredients include, but are not limited to, tacrolimus, pimecrolimus, sirolimus, acsomycin, everolimus. The topical pharmaceutical compositions of the present invention can also include one or more pharmaceutically acceptable excipients that are typically used in the art for locally applied semisolid dosage forms. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidant, buffering agent, binders, wetting agent, and the like and mixtures thereof.
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[0039] The foregoing macrolide related immunosuppressant ointment pharmaceutical
composition can be prepared by (a) dissolving a therapeutically effective amount of one or more active pharmaceutical ingredient comprising one or more macrolide related immunosuppressants or pharmaceutically acceptable salts or esters thereof in one or more of the foregoing penetration enhancers; (b) providing an ointment base; and (c) mixing the product of step (a) with the product of step (b).
[0040] Another embodiment of the present invention is a method for delivering a
macrolide related immunosuppressant through the skin of a mammal in order to treat conditions situated on and beneath the skin including at least the step of topically administering to the skin of the mammal an effective amount of a pharmaceutical ointment composition comprising (a) a therapeutically effective amount of one or more active pharmaceutical ingredient comprising one or more macrolide related immunosuppressants or pharmaceutically acceptable salts or esters thereof; (b) an ointment base; and (c) one or more skin penetration enhancers capable of percutaneous delivery of the macrolide related immunosuppressant through the skin. Conditions which can be treated employing the topical pharmaceutical compositions of the present invention include, but are not limited to, treatment of autoimmune related skin conditions and the like and combinations thereof.
[0041] The following examples are provided to enable one skilled in the art to practice
the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.
EXAMPLE 1
Ointment - Formula Composition I

Ingredients Category % w/w (in Example 1) Range which can be used(%w/w)
Tacrolimus(as Tacrolimus Monohydrate) API 0.10 0.01-5.00
N-Methyl Pyrolidone (Pharmasolve) Solubilizer &Penetration Enhancer 5.00 0.01-30.00
White Wax (White Bees Wax) Ointment Base/Emollient 6.70 20.0 - 99.90
Mineral Oil (Liquid Paraffin) 14.40
Paraffin (Hard Paraffin) 3.00
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Petrolatum, White 70.80
Total 100.00
[0042] The composition of this example was prepared as follows::
(1) Tacrolimus was dissolved in N-Methyl Pyrolidone.
(2) White Wax, Mineral Oil, Paraffin and White Petrolatum were melted together
at 70°C.
(3) The molten mass of step no. 2 was cooled to 40°C.
(4) The Tacrolimus solution of step no. 1 was added to the molten mass of step
no. 3 under gentle stirring.
(5) After the addition was completed, the mass was stirred gently for 5 minutes to
obtain an ointment having optimum and uniform consistency.
EXAMPLE 2
Ointment - Formula Composition

Ingredients Category % w/w (in Example 2) Range which can be used(% w/w/)
Tacrolimus(as Tacrolimus Monohydrate) API 0.10 0.01-5.00
N-Methyl Pyrolidone (Pharmasolve) Solubilizer &Penetration Enhancer 1.50 0.01-30.00
White Wax (White Bees Wax) Ointment Base 6.70 20.0-99.90
Mineral Oil (Liquid Paraffin) 14.40
Paraffin (Hard Paraffin) 3.00
Petrolatum, White 74.30
Total 100.00
[0043] The composition of this example was prepared in substantially the same manner
as the composition of Example 1 except that (1) white wax was used to increase the consistency of the ointment base and (2) hard paraffin was used as the stiffening agent in the ointment base.
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EXAMPLE 3
Ointment - Formula Composition

Ingredients Category % w/w(in Example2) Range which can be used(% w/w/)
Tacrolimus(as Tacrolimus Monohydrate) API 0.10 0.01-5.00
Transcutol P (Diethylene Glycol monoethyl ether. Solubilizer &PenetrationEnhancer 1.50 0.01-30.00
White Wax (White Bees Wax) Ointment Base 6.70 20.0-99.90
Mineral Oil (Liquid Paraffin) 14.50
Paraffin (Hard Paraffin) 3.00
Petrolatum, White 74.30
Total 100.00
[0044] The composition of this example was prepared as follows::
1. Oil phase: Melt white wax, hard paraffin, white petrolatum, and add mineral
oil, Maintain temperature of this phase to 70°C
2. Dissolve drug in diethylene glycol monoethyl ether under stirring. Ensure
complete drug dissolution.
3. Under homogenization add drug solution slowly in oil phase, homogenize for
15 minutes.
4. Allow to congeal under slow stirring.
[0045] While the above description contains many specifics, these specifics should not be
construed as limitations of the invention, but merely as exemplifications of preferred embodiments thereof. Those skilled in the art will envision many other embodiments within the scope and spirit of the invention as defined by the claims appended hereto.
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WHAT IS CLAIMED IS:
1. A pharmaceutical ointment composition comprising (a) a therapeutically effective amount of one or more active pharmaceutical ingredient comprising one or more macrolide related immunosuppressants or pharmaceutically acceptable salts or esters thereof; (b) an ointment base; and (c) one or more skin penetration enhancers capable of percutaneous delivery of the macrolide related immunosuppressant through the skin.
2. The pharmaceutical ointment composition of claim 1, wherein the macrolide related immunosuppressant is selected from the group consisting of tacrolimus, pimecrolimus, sirolimus, acsomycin, everolimus, pharmaceutically acceptable salts or esters thereof and mixtures thereof,
3. The pharmaceutical ointment composition of claim 1, wherein the skin penetration enhancer is one or more volatile organic solvents, one or more nonvolatile organic solvents and mixtures thereof.
4. The pharmaceutical ointment composition of claim 3, wherein the volatile organic solvents are selected from the group consisting of a C1-C20 aliphatic, cycloaliphatic and/or aromatic-aliphatic alcohols, each of which is monohydric or polyhydric, alcohol/water mixtures, saturated or unsaturated fatty alcohols having about 8 to about 18 carbon atoms, saturated or unsaturated fatty acids or esters thereof having about 8 to about 18 carbon atoms and mixtures thereof.
5. The pharmaceutical ointment composition of claim 3, wherein the volatile organic solvent is a C1-C20 alcohol.
6. The pharmaceutical ointment composition of claim 3, wherein the non-volatile organic solvents are selected from the group consisting of pyrrolidones, polyol ethers, polyols and mixtures thereof.
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7. The pharmaceutical ointment composition of claim 6, wherein the pyrrolidones are selected from the group consisting of N-alkylpyrrolidones, vinyl pyrrolidone, 2-pyrrolidone,-2-pyrrolidone-5-carboxylic acid, N-(2-hydroxyethyl)-2-pyrrolidone or fatty acid esters thereof, 1-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-tallowalkylpyrrolidones and mixtures thereof.
8. The pharmaceutical ointment composition of claim 6, wherein the pyrrolidone is N-methyl-2-pyrrolidone.
9. The pharmaceutical ointment composition of claim 6, wherein the polyol ethers are a C2-C30 polyol ether containing from 2 to about 10 hydroxyl groups.

10. The pharmaceutical ointment composition of claim 6, wherein the polyol ethers are selected from the group consisting of ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol monopropyl ether, ethylene glycol monophenyl ether, ethylene glycol monohexyl ether, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, triethylene glycol monobutyl ether, ethylene glycol monohexyl ether, diethyl glycol monohexyl ether, ethylene glycol phenyl ether. Glycols include, by way of example and without limitation, butylene glycol, propylene glycol, polypropylene glycol, polyethylene glycol, hexylene glycol, polyethylene glycol dodecyl ether, diethylene glycol monoethyl ether, polyethylene glycol-8-glyceryl caprylate, propylene glycol monocaprylate and the like and mixtures thereof.
11. The pharmaceutical ointment composition of claim 6, wherein the polyols are selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, hexylene glycol, propylene glycol monocaprylate and mixtures thereof.
12. The pharmaceutical ointment composition of claim 11, wherein the polyol ether is diethylene glycol monoethyl ether.
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13. The pharmaceutical ointment composition of claim 1, comprising about 0.01 to about 5 % w/w of the macrolide related immunosuppressant and about 0.01 to about 30 % w/w of the skin penetration enhancer.
14. The pharmaceutical ointment composition of claim 1, comprising about 0.02 to about 2 % w/w of the macrolide related immunosuppressant and about 1 to about 10 % w/w of the skin penetration enhancer.
15. The pharmaceutical ointment composition of claim 1, wherein the macrolide related immunosuppressant is tacrolimus or a pharmaceutically acceptable salts or ester thereof and the skin penetration enhancer is an N-alkylpyrrolidone.
16. The pharmaceutical ointment composition of claim 1, comprising about 0.01 to about 5 % w/w of tacrolimus and about 0.01 to about 30 % w/w of an N-alkylpyrrolidone.
17. The pharmaceutical ointment composition of claim 1, comprising about 0.02 to about 2 % w/w of tacrolimus and about 1 to about 10 % w/w of an N-alkylpyrrolidone.
18. The pharmaceutical ointment composition of claim 1, wherein the macrolide related immunosuppressant is tacrolimus or a pharmaceutically acceptable salts or ester thereof and the skin penetration enhancer is a polyol ether.
19. The pharmaceutical ointment composition of claim 1, wherein the macrolide related immunosuppressant is tacrolimus or a pharmaceutically acceptable salts or ester thereof and the skin penetration enhancer is a diethylene glycol monoethyl ether.
20. The pharmaceutical ointment composition of claim 1, comprising about 0.01 to about 5 % w/w of tacrolimus and about 0.01 to about 30 % w/w of a polyol ether.
19

21. The pharmaceutical ointment composition of claim 20, comprising about 0.01 to about 5 % w/w of tacrolimus and about 0.01 to about 30 % w/w of a diethylene glycol monoethyl ether.
22. The pharmaceutical ointment composition of claim 1, comprising about 0.02 to about 2 % w/w of tacrolimus and about 1 to about 10 % w/w of a polyol ether.
23. The pharmaceutical ointment composition of claim 22, comprising about 0.02 to about 2 % w/w of tacrolimus and about 1 to about 10 % w/w of a diethylene glycol monoethyl ether.
24. The pharmaceutical ointment composition of claim 1, further comprising one or more pharmaceutically acceptable excipients.
25. The pharmaceutical ointment composition of claim 1, further comprising one or more additional active pharmaceutical ingredients.
26. A process for preparing a pharmaceutical ointment composition comprising:

(a) dissolving a therapeutically effective amount of one or more active pharmaceutical ingredient comprising one or more macrolide related immunosuppressants or pharmaceutically acceptable salts or esters thereof in one or more skin penetration enhancers;
(b) providing an ointment base; and
(c) mixing the product of part (a) with the product of part (b).
27. The process of claim 26, wherein the macrolide related immunosuppressant is
selected from the group consisting of tacrolimus, pimecrolimus, sirolimus, acsomycin,
everolimus, pharmaceutically acceptable salts or esters thereof and mixtures thereof.
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28. The process of claim 26, wherein the skin penetration enhancer is one or more volatile organic solvents, one or more nonvolatile organic solvents and mixtures thereof
29. The process of claim 28, wherein the volatile organic solvents are selected from the group consisting of a C1-C20 aliphatic, cycloaliphatic and/or aromatic-aliphatic alcohols, each of which is monohydric or polyhydric, alcohol/water mixtures, saturated or unsaturated fatty alcohols having about 8 to about 18 carbon atoms, saturated or unsaturated fatty acids or esters thereof having about 8 to about 18 carbon atoms and mixtures thereof.
30. The process of claim 28, wherein the non-volatile organic solvents are selected from the group consisting of pyrrolidones, polyol ethers, polyols and mixtures thereof.
31. The process of claim 30, wherein the pyrrolidones are selected from the group consisting of N-alkylpyrrolidones, vinyl pyrrolidone, 2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, N-(2-hydroxyethyl)-2-pyrrolidone or fatty acid esters thereof, l-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-tallowalkylpyrrolidones and mixtures thereof.
32. The process of claim 30, wherein the polyol ethers are selected from the group consisting of ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol monopropyl ether, ethylene glycol monophenyl ether, ethylene glycol monohexyl ether, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monobutyl ether, diethylene glycol monobutyl ether, triethylene glycol monobutyl ether, ethylene glycol monohexyl ether, diethyl glycol monohexyl ether, ethylene glycol phenyl ether. Glycols include, by way of example and without limitation, butylene glycol, propylene glycol, polypropylene glycol, polyethylene glycol, hexylene glycol, polyethylene glycol dodecyl ether, diethylene glycol monoethyl ether, polyethylene glycol-8-glyceryl caprylate, propylene glycol monocaprylate and the like and mixtures thereof.
21

39. The method of claim 35, wherein the macrolide related immunosuppressant is tacrolimus or a pharmaceutically acceptable salts or ester thereof and the skin penetration enhancer is an N-alkylpyrrolidone.
40. The method of claim 35, wherein the pharmaceutical ointment composition comprises about 0.01 to about 5 % w/w of tacrolimus and about 0.01 to about 30 % w/w of an N-alkylpyrrolidone.
41. The method of claim 40, wherein the pharmaceutical ointment composition comprises about 0.02 to about 2 % w/w of tacrolimus and about 1 to about 10 % w/w of an N-alkylpyrrolidone
42. The method of claim 35, wherein the macrolide related immunosuppressant is tacrolimus or a pharmaceutically acceptable salts or ester thereof and the skin penetration enhancer is a polyol ether.
43. The method of claim 42, wherein the macrolide related immunosuppressant is tacrolimus or a pharmaceutically acceptable salts or ester thereof and the skin penetration enhancer is a diethylene glycol monoethyl ether.
44. The method of claim 35, wherein the pharmaceutical ointment composition comprises about 0.01 to about 5 % w/w of tacrolimus and about 0.01 to about 30 % w/w of a polyol ether.
45. The method of claim 44, wherein the pharmaceutical ointment composition comprises about 0.01 to about 5 % w/w of tacrolimus and about 0.01 to about 30 % w/w of a diethylene glycol monoethyl ether.
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46. The method of claim 35, wherein the pharmaceutical ointment composition
comprises about 0.02 to about 2 % w/w of tacrolimus and about 1 to about 10 % w/w of a polyol
ether.
47. The method of claim 46, wherein the pharmaceutical ointment composition
comprises about 0.02 to about 2 % w/w of tacrolimus and about 1 to about 10 % w/w of a
diethylene glycol monoethyl ether.
DATED THIS SIXTH (06TH) DAY OF MAY, 2005
24

ABSTRACT
A pharmaceutical ointment composition is provided comprising (a) a therapeutically effective amount of one or more active pharmaceutical ingredient comprising one or more macrolide related immunosuppressants or pharmaceutically acceptable salts or esters thereof; (b) an ointment base; and (c) one or more skin penetration enhancers capable of percutaneous delivery of the macrolide related immunosuppressant through the skin. Also provided is a process for its preparation and methods method for delivering a macrolide related immunosuppressant through the skin of a mammal in order to treat conditions situated on and beneath the skin.

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