FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
&
THE PATENTS RULE 2003 (SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"ATORVASTATIN COMPOSITION WITH IMPROVED BIOAVAILABILITY'
Glenmark Pharmaceuticals Limited
An Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House
HDO-Corporate Building, Wing -A
B. D. Sawant Marg
Chakala, Off Western Express Highway
Andheri [East], Mumbai 400099
India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION


“ATORVASTATIN COMPOSITION WITH IMPROVED BIOAVAILABILITY"
Field of Invention:
The present invention relates to the self emulsifying pharmaceutical compositions comprising hydroxymethylglutaryl (HMG) Coenzyme A-reductase (HMG-CoA reductase) inhibitors, more particularly atorvastatin or salts thereof.
Background of Invention:
Hydroxymethylglutaryl (HMG) Coenzyme A-reductase, an enzyme which limits the synthesis of cholesterol in the liver and stimulates the activity of the LDL (Low Density Lipoprotein) receptors. As a result of this mechanism of action, HMG-CoA reductase inhibitors are essentially used as hypocholesterolemic agents. A certain number of studies have moreover demonstrated that HMG-CoA reductase inhibitors have a preventive effect on cardiovascular diseases, and also that they induce a regression of atheromatous plaques. There are at present six HMG-CoA reductase inhibitors, which are, respectively, lovastatin, pravastatin, fluvastatin, simvastatin ,cerivastatin and, finally, atorvastatin , which is more particularly illustrated in the description hereinbelow.
Atorvastatin and pharmaceutically acceptable salts thereof, disclosed in U.S. Pat. No. 5,273,995 which is incorporated herein by reference is currently sold as Lipitor.RTM. having the chemical name [R--(R*,R*)]-2-(4-fluorophenyl)-.beta.,.delta.-d- ihydroxy-5-(1 -methyl ethyl)-3 -phenyl-4- [(phenylamino)carbonyl]-1 H-pyrrole-1 - heptanoic acid calcium salt (2:1) trihydrate .




Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase. As such, atorvastatin calcium is a potent lipid-lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent, as well as in the treatment of osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease.
Although. However its absorption is not perfect, only about 30 % of the applied dose is absorbed. See Corsini D. M. and coworker: Pharm. Res. 14 (11) Suppl.S253 (1997), which indicates that the systemic bioavailability of atorvastatin is only 12% of the dose ingested. The Applicant has also found that atorvastatin undergoes a strong first intestinal passage effect, a problem which, a priori, was not previously known for this molecule. A strong first intestinal passage effect is reflected in systemic bioavailability is only up to 12%.
Consequently, the problem which the invention proposes to solve is that of improving the systemic bioavailability of active principles liable to undergo a strong first intestinal passage effect by minimizing this effect rather than by blocking it. To do this, the invention provides a pharmaceutical composition for oral use in the form of a system which is self-microemulsifying on contact with an aqueous phase, the said system comprising: a therapeutically effective amount of the said active principle; a lipophilic phase and at least one surfactant stabilizer.
Example of self emulsifying system is described in U.S. Pat. No. 6,054,136 (Faraha et al). The invention relates to a composition which can be administered, in particular, orally, for pharmaceutical or cosmetic use, capable of forming a micro-emulsion in situ with the biological fluid of the body; the invention relates more especially to a composition providing of a self-micro-emulsifying carrier system for active agents, designated in the art by the English term "SMEDDS" (self-micro-emulsifying drug delivery system); these systems have the property of emulsifying in water at the temperature of the human body.


The self-microemulsifying systems which are of concern in the invention are known under the name SMEDDS.RTM., a trade mark registered by Gattefosse meaning Self Micro Emulsifying Drug Delivery System, and are described more particularly in document EP-A-670 715 and the corresponding document U.S. Pat. No. 6,054,136. The Applicant has found, equally surprisingly and unexpectedly, that the similar system makes it possible to reduce the intestinal metabolism of the atorvastatin and thereby to improve the systemic bioavailability of atorvastatin.
Other related arts to self-microemulsifying systems are
U.S. Pat. No. 5,965,160 "Self-emulsifiable formulation producing an oil-in-water emulsion" (Benita at al) comprising an oily component and a surfactant which itself is not an emulsion but rather self-emulsify, become or transformed into oil-in-water emulsion upon contact with water or body fluids. In contrast, the present invention composition is an emulsion itself, as is, before mixing with water and therefore a different physical form.
U.S. Pat. No. 5,993,858 "Method and formulation for increasing the bioavailability of poorly water-soluble drugs" (Amidon et al) a self-microemulsifying excipient formulation for increasing the bioavailability of a drug" "the range of concentration of the surfactant/co-surfactant broadly ranges from 15 to 90% (v/v) and more preferably ranges from approximately from 45% to 55% (v/v)." The present invention teaches much lower, about one tenth, surfactant concentration.
In the above mentioned documents, it is indicated that, as a result of the formation of the microemulsion on contact with an aqueous phase, SMEDDS.RTM. enable water-insoluble active principles to be dissolved, and consequently instantaneously by presenting them in the form of a multiparticulate supramolecular structure. The abovementioned documents therefore describe only the problem of solubility of the active principles, which is improved by the SMEDDS.RTM. formulation. However, no reference is made anywhere in these documents to the action of SMEDDS.RTM. on metabolism, in particular on intestinal metabolism.


It is known from the document EP1411895 that the incorporation of an active principle with a strong first intestinal passage effect into a self-microemulsifying system makes it possible to reduce the first intestinal passage effect, and thus to improve the systemic bioavailability of the active molecule. The system herein described is complicated that it needs specialized ingredients which are costly further this system contains triglycerides. The disadvantage of triglyceride-containing compositions is the dependence of therapeutic agent absorption on the rate and extent of lipolysis. Although colloidal emulsion particles can transport hydrophobic therapeutic agents through the aqueous environment of the gastrointestinal tract, ultimately the triglyceride must be digested and the therapeutic agent must be released in order to be absorbed through the intestinal mucosa. Thus the formulations described in the EP1411895 are still subject to the other disadvantages of pharmaceutical emulsions and triglyceride-based formulations as certain surfactants commonly used in the preparation of pharmaceutical emulsions, such as polyethoxylated castor oils, may themselves act as inhibitors of lipolysis. Although recent work suggests that certain surfactant combinations, when used in combination with digestible oils in emulsion preparations, can substantially decrease the lipolysis-inhibiting effect of some common pharmaceutical surfactants.
U.S. Pat. No 6652865 B2 "Method and formulation for decreasing statin metabolism". (Benamear et.al) This relates to pharmaceutical method and oral compositions comprising an active principle liable to undergo a intestinal passage effect and it discloses formulation of simvastatin containing PEG 8 caprilic/ capric glycerides, propylene glycol monolaurate and PEG 32 glyceryl laurate surprisingly during experimentation with atorvastatin in place of simvastatin we found that this formulation is physically unstable.
Thus, the Applicant of the present invention has found, entirely surprisingly, that the incorporation of an active principle with a strong first intestinal passage effect into a self-microemulsifying system comprising an oil in non-hydrous hydrophilic solvent, wherein the emulsifier stabilizer is present in a small but sufficient amount so that the composition is stable at room temperature and also facilitates the dissolution of the drug makes it
5

possible to reduce the first intestinal passage effect, and thus to improve the systemic bioavailability of the active molecule. The availability of the atorvastatin molecule in the liver is greater and the systemic passage is thus proportionally greater.
Summary of the Invention:
According to the present invention there is provided a pharmaceutical composition in the form of an non-hydrous emulsion with mean droplet size below one micron, comprising hydroxymethylglutaryl (HMG) Coenzyme A-reductase (HMG-CoA reductase) inhibitors, more particularly atorvastatin or salts that is dissolved, solubilized or dispersed in a non crystalline or low crystalline form in the composition, at least one lipophilic solvent comprising an internal phase ranges from 5% to 30%, at least one surfactant stabilizer with concentration from 20% to 50%, in a significant concentration, and a continuous non-hydrous hydrophilic external phase from 20% to 50% wherein said composition is easily mixed with body fluids to form homogeneous dispersion with mean particle size of less than one micron and improved solubilizing and dissolution of drug is obtained.
Objective of the Invention:
In one embodiment, this invention comprises an admixture of the atorvastatin or salts thereof, formulated in a non-hydrous emulsion, makes it possible to reduce the first intestinal passage effect, and thus to improve the systemic bioavailability of the atorvastatin or salts thereof.
In another embodiment, the invention provides a method for enhancing the dissolution and oral availability of a pharmacologically active agent having low or poor water solubility, wherein the method comprises oral administering of the patient undergoing treatment a mixture of the atorvastatin or salts thereof in the solubilizing and dissolution facilitating composition as described herein.
It has been unexpectedly found that despite using very specific and simple ingredients in minimum concentration in the current invention composition, adequate solubilization and systemic bioavailability of the atorvastatin or salts thereof is achieved.


In another embodiment, the invention provides a process for the preparation of stable pharmaceuticals composition comprising a) Mixing of surfactant and non-hydrous hydrophilic solvent by gentle stirring until clear homogenous mixture forms, to this (b) Addition of atorvastatin calcium, slowly with gentle stirring at 50°C under water bath till it becomes clear and then (c) Add lipophilic Phase with gentle stirring. The resulting composition may be dosed directly for oral administration, diluted into an appropriate vehicle for oral administration, filled into capsules either soft gelatin capsule or hard gelatin capsule or hard vegetable capsules, or adsorbed on to the inert ingredients to compressed into tablets or delivered by some other means obvious to those skilled in the art
In another embodiment, the invention provides tablets composition of the atorvastatin or salts thereof.
In another embodiment, the invention provides preparation of tablets composition of the comprises a) drug concentrate of atorvastatin or salts thereof in surfactant, non-hydrous hydrophilic solvent and Lipophilic Phase (b) adsorption of drug concentrate on to the inert ingredients (c) lubrication of drug adsorbate and d) compression into tablets.
Detailed description of Invention:
The present invention provides in one aspect a composition comprising an oil in non-hydrous hydrophilic solvent emulsion comprising: (a) Atorvastatin or salts thereof, and (b) At least one lipophilic solvent comprising the internal phase of the emulsion, and (c) at least one surfactant stabilizer, and (d) a continuous non-hydrous and hydrophilic phase, wherein enhanced solubilizing effect with reduced first intestinal passage effect, and thus to improve the systemic bioavailability of the atorvastatin or salts thereof is obtained.
The pharmaceutical compositions of the present invention includes, but not limits to, hard gelatin capsules, soft gelatin capsules, tablets, liquid orals, gels, ointments, cream, suppositories.


Self-microemulsifying systems dug delivery system ("SMEDDS") is a mixture of lipid, surfactant, and cosurfactant, which are emulsified in aqueous medium under gentle digestive motility in the gastrointestinal tract.
"Lipophilic solvent" is any pharmaceutical or food approved substance which is oily in
its nature that is not mixing or dissolving with water or hydrous mediums. Such lipophilic
solvent may be natural or synthetic or semi-synthetic, in the form of liquid, semi-solid or
solid at room temperature. Example of lipophilic solvents are mineral oil, vegetable oil,
silicon oil, lanolin, refined animal oil, hydrocarbon esters derived from vegetable animal
or marine origin.
Example of vegetable oils are: isopropyl miristate, jojoba oil, almond oil, avocado oil, coconut oil, capric-caprylic tryglyceride of fractionated coconut oil, nutmeg oil, PEG-6 apricot kernel oil (Oleoyl Polyoxylglycerides: Labrafil.RTM. M 1944 CS), castor oil, olive oil and oleic acid, soybean oil, sunflower oil, canola oil etc. The oil may be saponifiable or unsaponifiable and liquid or solid at room temperature.
Special oils are essential oils or poly unsaturated fatty acid or oils or etherified oils and
modified semi-synthetic oils. Example of semi-synthetic oil is a product of inter-
esterification of hydrogenated palm oil palm kernel oil (C8-C18 triglycerides) with
melting point at 30.degree. C.-50.degree. C.
A further preferred class of hydrophobic solvents may be selected from the group comprising isostearic acid derivatives, isopropyl palmitate, lanolin oil, diisopropyl dimerate, maleated soybean oil, octyl palmitate, isopropyl isostearate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, isopropyl palmitate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, hydrogenated coco-glycerides, isononyl isononanoate, isotridecyl isononanoate, myristal myristate, isocetyl


stearate

and

isoadipate.

A further class are fatty acids include, but are not limited to, caproic acid, capric acid, caprylic acid, oleic acid, palmoic acid, stearic acid, linoleic acid, octanoic acid, decanoic acid, linolenic acid, palmitic acid, palmitoleic acid, arachidic acid, myristic acid, behenic acid and lignic acid, or fatty alcohols, and also mono and diglycerides.
The "surfactant" is any surface active agent of pharmaceutical cosmetic or food grade
that has an amphiphilic nature and that is able to stabilize the emulsion. The surfactant
can by hydrophilic, hydrophobic, or a mixture of hydrophilic and hydrophobic
surfactants. Examples are Polyethoxylated Fatty Acids, PEG-Fatty Acid Diesters, EG-
Fatty Acid Mono- and Di-ester Mixtures, Polyethylene Glycol Glycerol Fatty Acid
Esters, Alcohol-Oil Transesterification Products, Polyglycerized Fatty Acids, Propylene
Glycol Fatty Acid Esters, Mixtures of Propylene Glycol Esters—Glycerol Esters, Mono-
and Diglycerides, Sterol and Sterol Derivatives, Polyethylene Glycol Sorbitan Fatty Acid
Esters, Polyethylene Glycol Alkyl Ethers, Sugar Esters, Polyethylene Glycol Alkyl
Phenols, Polyoxyethylene-Polyoxypropylene Block Copolymers, Sorbitan Fatty Acid
Esters, Ionic Surfactants.
Preferred stabilizing emulsifiers are non-ionic and PEG free surface active agents, such as: non ionic condensate of a carbohydrate and fatty acid, such as; Sucrose esters of fatty acids and Glucosides of fatty acids and Sorbitan esters of fatty acids, various esters of mono-and diglycerides of fatty acids and sucroglycerides, Ascorbic acid esters, Glycerin esters, cetearyl glucosides, Polyacids carbohydrate esters of fatty acids, Citric acid esters of fatty acids, and the colloidal gums and the like.
Further examples of preferred surfactant stabilizers are polyglyceryl fatty acids esters such as Polyglyceryl- 10-fatty acid, for example; Polyglyceryl-10-tetralinoleate or Polyglyceryl- 10-oleate or Polyglyceryl- 10-stearate or Polyglyceryl- 10-laurate.
Further examples of preferred surfactant stabilizers are amphiphylic polymers such


cellulose derivatives (methyl cellulose, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, ethyl cellulose), and acrylate derivatives such as Pemulene.RTM. types from BFGoodrich USA. Also colloidal silica or natural gums such as, Xanthan gum and microcrystalline cellulose and microcrystalline cellulose blends with sodium carboxymethyl cellulose are practical emulsifiers stabilizing agents.
Preferred sucrose esters are sucrose stearate and sucrose palmitate (Sisterna SP50 and SP50C or Sistema SP70) that are blends with free mono esters. Preferred HLB of surfactants surfactant stabilizers is 6 to 18 and more preferably 10 to 15.
The non-hydrous hydrophilic solvent is made of organic solvents that are completely and
immediately miscible with water and physiological fluids.
Preferred pharmaceutically acceptable water-miscible non-aqueous solvents suitable for
use in the non-aqueous compositions of this invention include, but are not limited to,
glycols such as propylene glycol and glycerin, polyethylene glycols of various molecular
weights and the like and their mixtures.
Less preferable are organic solvents that are only moderately or partially miscible with water.
Example of other preferred solvents and possible co-solvents are: polyols or amides or esters, butanediols and isomers thereof, pentaerythritol, sorbitol, mannitol, dimethyl isosorbide, polypropylene glycol, ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG or methoxy PEG; Amides, such as 2-pyrrolidone, 2-piperidone, F-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide; Esters, such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl butyrate, triacetin, propylene glycol diacetate, .epsilon.-caprolactone and isomers thereof, .delta.-valerolactone and isomers thereof, .beta.-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, transcutol. Mixtures


and any combination of above solvents are most preferable.
The lipophilic solvent in non-hydrous emulsion composition may further comprise excipients or inactive ingredients or additives, such as stabilizers, colorants, polymers, antioxidants, flavoring and fragrance, neutralizing agents and fillers.
In accordance to one of the preferred embodiments of the present invention drug concentrate adsorbed onto the "adsorbate" is any pharmaceutical or food approved inert ingredients comprises silicone dioxide like Colloidal silicon dioxide, Magnesium aluminium silicate, microcrystalline cellulose, Croscarmellose sodium, lactose, mannitol, dibasic calcium phosphate, calcium sulphate, , dextrates, dextrin, sucrose, sorbitol, calcium carbonate, magnesium carbonate, kaolin, maltodextrin, starches, pregelatinized starch and tricalcium phosphate and the like.
In accordance to one of the preferred embodiments of the present invention the formulation is made available in a shell, preferably soft shell, wherein the said shell essentially comprises of gelatin, glycerin, water and one or more of preservatives, like methyl paraben, propyl paraben, and one or more of colorants, like iron oxide black, titanium dioxide.
Other required pharmaceutically acceptable excipients selected form amongst the diluents, binders, disintegrants, glidants and lubricants for the preparation of capsules or tablets dosage form. The binders are selected from the group comprising of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose and polyethylene glycol. The diluents are selected from the group comprising of lactose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, calcium sulphate, dextrates, dextrin, sucrose, sorbitol, calcium carbonate, magnesium carbonate, kaolin, maltodextrin, starches, pregelatinized starch and tricalcium phosphate. The disintegrants are selected from the group comprising of crospovidone, croscarmellose sodium, croscarmellose calcium, sodium starch glycolate, and low substituted hydroxypropyl cellulose, starch and magnesium aluminium silicate. The


glidants are selected from the group comprising of colloidal silicon dioxide and talc. The lubricants are selected from the group comprising of magnesium stearate, calcium stearate, hydrogenated vegetable oil, paraffin, polyethylene glycol, sodium benzoate, zinc stearate, stearic acid and talc.
In accordance to the preferred embodiment of the present invention, the formulation having presently disclosed composition and prepared in accordance to the preferred method, as described herein above is filled in the shell, preferably in the soft shell, more preferably in the disintegrating soft gelatin shell, which becomes part of the formulation for oral administration and it can not be separate entity of the medicament taken by the patient.
Following Examples are just an illustration of the present invention and doesn't limit the scope of invention.
Example L Manufacturing of atorvastatin self micro emulsifying drug delivery system:-
Table 1

Sr. No. Ingredients Specification Percentage %
1 AtorvastatinCalcium(Amorphous) eq. to Atorvastatin Inhouse 5
2 LabrafilM1944CS USP-NF 15
3 Cremophor EL USP-NF 40
4 Propylene Glycol USP-NF 40
Manufacturing of process:-
Step I -Cremophor EL and propylene glycol were mixed by gentle stirring until clear homogenous mixture form.
Step II - Atorvastatin calcium (amorphous) was then added slowly with gentle stirring to step I mixture at 50°C, stirring continued till the mixture becomes clear.
Step III - To the mixture in step II labrafil M 1944 CS (previously warmed to 50°C) was then added with gentle stirring.


Step III - The mixture of step III then cooled down to room temperature under stirring and filled into soft gelatin capsules.
Example 2\ Manufacturing of atorvastatin tablets:-
A) Preparation of Drug Concentrate-Tablet 2

Sr.No. Ingredients Specification Qty/Batch In gram
1 AtorvastatinCalcium(Amorphous) eq. to 8% Atorvastatin Inhouse 8.46
2 Labrafil M 1944 CS USP-NF 15.00
3 Cremophor EL USP-NF 38.275
4 Propylene Glycol USP 38.275
Step I -Cremophor EL and propylene glycol were mixed by gentle stirring until clear homogenous mixture form.
Step II - Atorvastatin calcium (amorphous) was then added slowly with gentle stirring to step I mixture at 50°C, stirring continued till the mixture becomes clear.
Step III - To the mixture in step II labrafil M 1944 CS (previously warmed to 50°C) was then added with gentle stirring.
Step HI - The mixture of step III then cooled down to room temperature under stirring.
B) Preparation of Adsorbate and granulation-Table 3

Sr. No. Ingredients Specification Qty/Batch In gram
1 Colloidal silicon dioxide USP-NF 38.75
2 Magnesium aluminium silicate USP-NF 38.75
3 SMEDDS concentrate (of step HI) In house 100.00
4 PVP K-30 (povidone K30 ) USP 5.00
5 Isopropyl alcohol* USP 40.00
Total - 182.5
*Does not appear in the final formulation.


Step IV- The concentrate from Step III was added on to the mixture of colloidal silicon dioxide and magnesium aluminum silicate in 1:1 proportion placed in a planetary mixture and mixed to obtain uniform mixture.
Step V- The adsorbate of Step IV was then granulated using the solution of povidone K30 in Isopropyl alcohol and dried into Fluid Bed Granulator/ tray dryer, the dried granules then sifted through 20 mesh sieve.
Step VI-The granules of Step V were analyzed for the atorvastatin content, based on analytical results the granules equivalent to 20mg of Atorvastatin were taken for the lubrication.
C) Compression-
Table 4

Sr. No. Ingredients Specification Quantity /tablet in mg
1 Adsorbate eq. to 20mg Atorvastatin Granules from step VI (added as Atorvastatin calcium) In-house 456.00
5 Prosolv SMCC 90 In-house 66.00
5 Calcium carbonate USP 30.00
6 Croscarmellose sodium USP-NF 30.00
7 Talc USP 12
8 Magnesium stearate USP-NF 6
Total weight 600 mg
Step VII-Granules from Step VI were mixed with Prosolv SMCC 90, Calcium carbonate, Croscarmellose sodium, talc and magnesium stearate in cone blender. Step VII-Blend from Step VIII, then compressed in to tablets.


It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.