The present invention relates to stable ointment comprising medicament, carboxyvinyl polymer, non aqueous-water miscible solvent base and/or oleagineous base, and the process of preparation thereof.
Ointments are one of the oldest vehicles used for the incorporation of medicaments applied topically. The ointment vehicle provides a means of distributing the medication uniformly over the affected skin surface and maintaining it there for a sufficient period of time to get the therapeutic effect. In low dose steroid compositions, the ointment vehicle may comprise as much as 99% of the total composition. Therefore the ointment vehicle in which the steroid is incorporated is as important as the steroid molecule itself in determining the potency of a given composition, because the vehicle affects the amount of steroid that is released and absorbed in any given period of time.
An ideal ointment should allow the complete release of the medicament, and should assist in good penetration into the skin through one or the other mechanisms. Further, aqueous based ointments are desirable, as water is required to improve the degree of water washability and thus to enhance the cosmetic value of the compositions. Prior art patents such as US 4,489,070 and US 7,220,424 suggest the use of water, to formulate steroids. Since most of the steroids are water-insoluble, these when dispersed or incorporated in any aqueous based ointments or in oil-in-water/water-in-oil emulsion-based vehicle, may not be completely absorbed through the skin. Further, it has been observed that the steroids tend to crystallize out from these aqueous based ointments in due course of time.
In order to obviate the disadvantages of utilizing a water-containing composition, alternative ointment vehicles for these steroids, are the oleaginous bases which form an occlusive covering on the skin, thereby inducing skin hydration through sweat accumulation at the skin-ointment interface. Prior art lists number of references such as US 3,952,930, US 3,892,856, US 4,017,615, US 4,070,462, US 4,083,974, US 5,993,787 and US 7,179,475 which are free of water. However, proper dispersion of the

steroid in such oleaginous bases is a major problem that results in inefficient absorption. Further, these ointments are greasy and difficult to remove from the skin and clothing, due to their lack of water-washability.
Therefore there remains a need for stable ointment which overcomes the crystallization, incorporation and the absorption problems of the aqueous based ointments, and the greasiness and removability aspects of oleaginous bases.
We have now discovered a stable ointment with an improved washability and minimum greasiness which can easily incorporate and further release the medicament almost completely. The ointment of the present invention comprises carboxyvinyl polymer and non aqueous-water miscible solvent base and/or oleagineous base.
Hence in one general aspect there is provided a stable ointment comprising medicament, carboxyvinyl polymer, and non aqueous-water miscible solvent base and/or oleagineous base.
In another general aspect there is provided a stable ointment comprising steroid, carboxyvinyl polymer, and non aqueous-water miscible solvent base and/or oleagineous base.
In another general aspect there is provided a stable ointment comprising medicament, from about 0.5% to about 10% w/w of carboxyvinyl polymer based on the total weight of the ointment, and non aqueous-water miscible solvent base and/or oleagineous base.
In another general aspect there is provided a stable ointment comprising steroid, from about 0.5% to about 10% w/w of carboxyvinyl polymer based on the total weight of the ointment, and non aqueous-water miscible solvent base and/or oleagineous base.

In another general aspect, there is provided a stable ointment, which may be prepared by a process comprising the steps of:
(a) dissolving/dispersing medicament and one or more pharmaceutically
acceptable inert excipients into non aqueous-water miscible solvent
base base and/or oleagineous base using appropriate techniques; and
(b) dissolving/dispersing carboxyvinyl polymer into the mixture of step (a)
to obtain the ointment.
The term "stable" as used herein means that the ointment maintains its physicochemical properties in due course of time at room temperature and the medicament, in particular steroids, do not crystallize out in due course of time at room temperature.
The term "medicament" as used herein includes one or more medicament having the desired pharmacological activity. These include steroids, antihistamines such as diphenhydramine, local anesthetics such as lidocaine and benzocaine, keratolytics such as sulfur and salicylic acid, antipsoriatic drugs such as anthralin, antiviral drugs such as acyclovir, fluorouracil, antimicrobials such as antibiotics, antifungals, antiseptics such as zinc oxide, retinoids such as tretinoin, and other topically active drugs, in particular steroids.
The term "steroid" as used herein includes corticosteroids or anabolic steroids, having a hydrogenated cyclopentoperhydrophenanthrene ring system, in particular corticosteroids. Corticosteroids are released by the adrenal cortex (except sex hormones of adrenal origin) in response to the release of adrenocorticotrophin or adrenocorticotropic hormone by the pituitary gland, or to any synthetic equivalent, or to angiotensin II. Examples of corticosteroids include but are not limited to alclometasone dipropionate, amcinonide, amcinafel, amcinafide, beclamethasone, betamethasone, betamethasone dipropionate, betamethasone valerate, clobetasone propionate, chloroprednisone, clocortelone, cortisol, cortisone, cortodoxone, difluorosone diacetate, descinolone, desonide, defluprednate, dihydroxycortisone, desoximetasone, dexamethasone, deflazacort,

diflorasone diacetate, dichlorisone, esters of betamethasone, flucetonide, flucloronide, fluorocortisone, flumethasone, flunisolide, fluocinonide, fluocinolone acetonide, flucortolone, fluperolone, fluprednisolone, fluroandrenolone acetonide, fluocinolone acetonide, flurandrenolide, fluorametholone, fluticasone propionate, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, hydrocortamate, medrysone, meprednisone, methylprednisone, methylprednisolone, mometasone furcate, paramethasone, prednisone, prednisolone, prednidone, triamcinolone acetonide, and triamcinolone, in particular betamethasone and beclomethsone. Examples of anabolic steroids include testosterone, estradiol, spironolactone and the like. The amount of steroid may vary from about 0.001% to about 0.25% w/w, in particular from about 0.015% to about 0.15% w/w, based on the total weight of the ointment.
The term "carboxyvinyl polymer" as used herein is a homopolymer, which is a crosslinked compound containing one or more monomers derived from acrylic acid, substituted acrylic acids, and salts and esters of these acrylic acids and the substituted acrylic acids, wherein the crosslinking agent contains two or more carbon-carbon double bonds and is derived from a polyhydric alcohol. The 0.5% w/w aqueous dispersion/solution of carboxyvinyl polymer, at pH 7.5, may have a viscosity range from about 30,000 to about 70,000 cps, in particular from about 40,000 to about 60,000 cps. These carboxyvinyl polymers contains carboxylic residue in the ratio of about 56.0 to 68.0%. These indicate a pH of 2.5 to 3.0 when dispersed in 1% aqueous solution. Commercially carboxyvinyl polymer is available as Carbopol™ 900 series from B.F. Goodrich such as Carbomer 934, Carbomer 934P, Carbomer 940, Carbomer 974P or Carbomer 980. The amount of the carboxyvinyl polymer may vary from about 0.5% to about 10% w/w, in particular from about 1% to about 5% w/w, based on the total weight of the ointment.
The ointment of the present invention is either completely free of water or comprises water not more than 2% w/w based on the total weight of the ointment.

The term "oleaginous base" as used herein includes any oily or greasy material and, preferably, is selected from the group consisting of paraffins or a combination of paraffins ranging from liquids (e.g., mineral oil) to semisolids (e.g., petrolatum and white petrolatum) to solids (e.g., paraffin wax); silicones (known as polysiloxanes), lanolins, including anhydrous lanolin and essentially anhydrous derivatives thereof; and the like.
The term "non aqueous-water miscible solvent base" as used herein is a glycol solvent selected from the group consisting of propylene glycol, butylene glycol, hexylene glycol and the like, in particular propylene glycol.
The ointment of the present invention may further include one or more pharmaceutically acceptable inert excipients.
The term "pharmaceutically acceptable inert excipients" as used herein includes surfactants, thickeners, solubilizers, auxiliary solvents, buffers, penetrants, stabilizers, preservatives, pH adjusters, anti-foaming agents, anti-whitening agents, colors, and fragrances. These excipients may be added to improve consistency, homogeneity, spreadability, texture and appearance of the ointment.
Examples of the surfactants include, but not are limited to, any of the nonionic, amphoteric, anionic, and cationic surfactants such polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; Sterol and sterol derivatives, for example sitosterol; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol -20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for

example sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer" and the like.
Examples of the thickeners include, but are not limited to, colloidal alumina, colloidal silicon, polyethylene, natural waxes (including spermaceti and white beeswax), fatty acids (such as stearic acid), fatty alcohols (such as cetyl alcohol and stearyl alcohol), fatty acid esters of alcohols having from about 3 to about 16 carbon atoms such as myristyl stearate and cetyl stearate, fatty amides having from 10-22 carbon atoms, synthetic waxes, microcrystalline waxes, paraffin waxes, cellulose derivatives (such as hydroxypropylcellulose); and natural gums (such as tragacanth) and monoglycerides such as glyceryl monostearate and glyceryl monopalmitate, and the like.
Examples of solubilizers include, but are not limited to, straight chain as well as branched chain aliphatic and aromatic alcohols having five or more than five carbon atoms.
Examples of auxiliary solvents, include, but are not limited to, polyethylene glycols, propylene carbonate; glycerin; and polypropylene glycols, said polyethylene and polypropylene glycols having molecular weights from 100 to 20,000; benzyl alcohol; and the like.
Examples of suitable buffers, include, but not limited to, organic acids (such as citric acid), salts of organic acids (such as sodium citrate), inorganic acids (such as phosphoric acid), inorganic bases (such as sodium hydroxide), inorganic salts (such as sodium biphosphate), and the like.
Examples of penetrants include, but are not limited to, dimethylformamide, dimethylacetamide, tetrahydrofuran, tetrahydrofurfuryl alcohol, and 1-dodecylazacycloheptan-2-one, and dialkyl sulfoxides having from 2 to 22 carbons per alkyl group, such as dimethylsulfoxide. including glycols, e.g., propylene glycol, glycerol and butylene glycol; glycol mono- and di-ethers marketed under the trade names Dowanol® and Pyroglydes®; polyoxyethylenated glycerides marketed under the trade name Labrosol®;

dimethylsulphoxide, caprolactam, N-methyl-pyrrolidone-2, ethyl lactate, and the like.
Examples of stabilizers include, but are not limited to, antioxidants (such as ascorbic acid, alpha-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, and ascorbyl palmitate); chelating agents (such as ethylenediamine tetraacetic acid and its salts); and ultraviolet (UV) absorbers (such as benzophenone-3).
Examples of preservative include, but are not limited to, imidurea, benzyl alcohol, methylparaben, propylparaben, butylparaben, sorbic acid, potassium sorbate, dehydroacetic acid, sodium dehydroacetate, chloroxylenol, and quaternium-15.
Examples of pH adjusters include, but are not limited to, acids, bases and buffers. Suitable acids include hydrochloric acid, phosphoric acid, lactic acid; suitable bases include diethanolamine, triethanolamine, sodium hydroxide; and suitable buffers include phosphates such as monobasic sodium phosphate, and dibasic sodium phosphate, lactates, and citrates and the like.
Examples of anti-foaming anti-whitening agents include silicone fluid, and the like.
The colors and fragrances may include any FDA approved colors and fragrances
The ointment of the present invention may be prepared by conventional methods known in the art of making topical compositions. Such methods typically involve mixing of the ingredients in one or more steps to a relatively uniform state, with or without heating, cooling, application of vacuum, and the like. Solids materials may be dissolved in liquid materials, dispersed using high shear, or melted to facilitate incorporation into the ointment vehicle. The processing equipment that may be used to manufacture the vehicle may include heated or steam jacketed kettles, propeller mixers, homogenizing

mixers, heat exchanger, colloid mills, roller mills, and kettles with side-scraping mixers.
In one of the embodiment, the stable ointment vehicle with an improved washability, and minimum greasiness may be prepared by a process comprising the steps of:
(a) dissolving/dispersing one or more steroid and pharmaceutically
acceptable inert excipients into glycol using appropriate techniques;
and
(b) dissolving/dispersing carboxyvinyl polymer into the mixture of step (a)
to form an ointment.
The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any way.
Example 1-2
(Table Removed)

Procedure:
1. A portion of polyethylene glycol 400 was weighed in SS vessel and heated the bulk to 45-50°C.

2. Salicylic acid was added and dissolved in the bulk of step 1 under
stirring.
3. Butylated hydroxyl toluene was added and dissolved in the bulk of step
2 under stirring.
4. Betamethasone dipropionate was dispersed in a portion of
polyethylene glycol 400 and passed in twice through the colloid mill.
5. The bulk of step 4 was transferred to the bulk of step 3 and mixed.
6. The colloid mill was rinsed with the remaining portion of polyethylene
glycol 400 and added to the bulk of step 5 and mixed.
7. Zinc oxide was dispersed in a portion of propylene glycol under stirring.
8. The bulk of step 7 was transferred into the bulk of step 6 and mixed.
9. Disodium edetate was dispersed in a portion of propylene glycol and
recycled it through colloid mill at minimum clearance for 15-20 minutes.
10. The bulk of step 9 was transferred into the bulk of step 8 through
muslin cloth under fast stirring.
11. The colloid mill was rinsed with a small amount of propylene glycol and
added to the bulk of step 10 and mixed.
12. The remaining quantity of propylene glycol was added and mixed in the
bulk of step 11 under stirring for not less than 10 minutes.
13.Carbomer 940 was dispersed into the bulk of step 12 under high speed stirring with homogenizer "on" for 3-4 hours or till homogeneous lump free dispersion is obtained.
14. The weight was made up with propylene glycol and stirred at slow
speed.
15. The ointment of step 14 was filled into previously cleaned tubes.
Example 3
(Table Removed)

Procedure:
1. A portion of polyethylene glycol 400 was weighed in SS vessel and
heated the bulk to 45-50°C.
2. Salicylic acid was added and dissolved in the bulk of step 1 under
stirring.
3. Butylated hydroxyl toluene was added and dissolved in the bulk of step
2 under stirring.
4. Beclomethasone dipropionate was dissolved in the remaining quantity
of polyethylene glycol 400 under stirring.
5. The bulk of step 4 was transferred to the bulk of step 3 and mixed.
6. Disodium edetate was dispersed in a portion of propylene glycol and
recycled it through colloid mill at minimum clearance for 15-20 minutes.
7. The bulk of step 6 was transferred into the bulk of step 5 through
muslin cloth under fast stirring.
8. The colloid mill was rinsed with a small amount of propylene glycol and
added to the bulk of step 7 and mixed.
9. The remaining quantity of propylene glycol was added and mixed in the
bulk of step 8 under stirring for not less than 10 minutes.
10. Carbomer 940 was dispersed into the bulk of step 9 under high speed
stirring with homogenizer "on" for 3-4 hours or till homogeneous lump
free dispersion is obtained.
11. The weight was made up with propylene glycol and stirred at slow
speed.
12.The ointment of step 11 was filled into previously cleaned tubes.

Three batches as per the composition of example 1, three batches as per the composition of example 2 and three batches as per the composition of example 2 were prepared and stored at 30±2° C and 75±5% for a period of 6 months, and analyzed for betamethasone, beclomthasone, salicylic acid and zinc oxide contents using validated in house analytical methods.
(Table Removed)

The results of the stability studies indicate that the compositions of the present invention are stable and comply with the regulatory requirements.

WE CLAIM:
1. A stable ointment comprising a medicament, carboxyvinyl polymer, and
a non aqueous-water miscible solvent base and/or oleagineous base.
2. The stable ointment of claim 1, wherein the medicament is a steroid.
3. The stable ointment of claim 1, wherein steroid is present in an amount
of 0.001% to 0.25% w/w, based on the total weight of the ointment.
4. The stable ointment of claim 1, wherein the carboxyvinyl polymer may
have a viscosity from 30,000 to 70,000 cps.
5. The stable ointment of claim 4, wherein the carboxyvinyl polymer is
present in an amount of 0.5% to 10% w/w based on the total weight of
the ointment.
6. The stable ointment of claim 1, wherein the oleaginous base is
selected from the group consisting of paraffins, silicones and lanolins.
7. The stable ointment of claim 1, wherein the non aqueous-water
miscible solvent base is a glycol selected from the group consisting of
propylene glycol, butylene glycol and hexylene glycol.
8. The stable ointment of claim 1, wherein the ointment may further
comprise one or more pharmaceutically acceptable inert excipients
selected form the group consisting of surfactants, thickeners,
solubilizers, auxiliary solvents, buffers, penetrants, stabilizers,
preservatives, pH adjusters, anti-foaming agents, anti-whitening
agents, colors, and fragrances.

9. The stable ointment vehicle of any of the preceding claims, wherein the
ointment may be prepared by a process comprising the steps of:
(a) dissolving/dispersing medicament and one or more
pharmaceutically acceptable inert excipients into non aqueous-
water miscible solvent base and/or oleagineous base using
appropriate techniques; and
(b) dissolving/dispersing carboxyvinyl polymer into the mixture of
step (a) to obtain an ointment
10. A stable ointment and process of preparation thereof, as described and
illustrated in the examples herein.