FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
COMPLETE SPECIFICATION
(SECTION 10; RULE 13)
TITLE:
"PHARMACEUTICAL FORMULATION OF DABIGATRANETEXILE METHYL SULFONATE"
APPLICANT:
V-ENSURE PHARMA TECHNOLOGIES PRIVATE LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT MUMBAI, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED FIELD OF THE INVENTION
The present invention relates to a novel pharmaceutical formulation Dabigatran etexile methyl sulfonate or its pharmaceutically acceptable salts thereof which contains organic acids to increase the solubility. Further, the present invention provides the pellets, which are preparedwith the aid of solvents and sprayed on to the inert core. This instant invention also provideapharmaceutical formulation wherein the preparation of pellets of Dabigatran etexile methyl sulfonate and the pellets of tartaric acid and filling of both the pellets into the HPMC capsule with or without carrageenan.
BACK GROUND OF THE INVENTION
Dabigatran is marketed in the form of pellets in HPMC capsules under the trade name
PRADEXA(R). The product contains 75,110, 150 mg of dabigatran etexilate in the form of
methanesulfonate salt, and the pellets further contain tartaric acid, acacia (gum arabic),
hypromellose (HPMC,hydroxypropylmethylcellulose), dimeticone 350
(dimethylpolysiloxane), talc and hydroxypropylcellulose (HPC).
Dabigatran etexilate having the chemical formula (I) is already known from WO 98/37075, which discloses compounds with a thrombin- inhibiting effect and the effect of prolonging the thrombin time, under the name 1 -methyl- 2-[N-[4-(N-n-hexyloxycarbonyl amidmo)phenyl]-amino-methyl]-benzimidazole-5-yl- carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amides. The compound of formula (I) is a double prodrug of the compound (II) i.e. the compound of formula (I) is only converted into the active compound of formula (II) after entering the body. The main indication for the compound of chemical formula (I) is the post-operative prevention of deep-vein thrombosis. It is expected that it will also be used for the treatment of cardiovascular events in the future.


The solubility of dabigatran, dabigatran etexilate and dabigatran etexilate methanesulfonate in particular, is strongly dependant on the pH value, with increased solubility at acidic pH. On the other hand, it is chemically instable in acidic environment and particularly susceptible to hydrolysis of the pro-drug forming moieties.
The production of PRADEXA(R) and the powder layering method according to which it is prepared are described in detail in patent applications WO03/074056, WO2009/118321, WO2009/118322, and WO2010/007016.
WO03/074056 discloses the use of pharmaceutically acceptable organic acids with a water solubility of >1 g/250 ml at 20°C, preferably >1 g/160 ml at 25°C in solid oral preparations, and in particular methanesulphonic acid addition salt of dabigatran etexilate (dabigatran etexilate methanesulphonate). The disclosed pharmaceutically suitable acids are for example tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid including the hydrates and acidic salts thereof which are applied to the pellets by powder layering. A preferred embodiment of WO03/074056 is a multiparticulate preparation, in particular so-called pellet formulations may be used. The roughly bead-shaped/spherical core region of the pellet consists of a pharmaceutically acceptable organic acid. Then follows the isolating layer, which separates the acid core from the layer containing the active substance. The isolating layer is in turn surrounded by the equally spherically shaped layer of the active substance which may in turn be enclosed in an over-coating which increases the abrasion resistance and shelf life of the pellet.

WO2009/118321 discloses a process for the preparation of approximately sphericaltoall-shaped tartaric acid pellets suitable for the manufacture of drug formulations containing active ingredients, the pellets so obtained as such, and the use thereof as a starting material for the production of drug formulations containing active ingredients. The process is characterized in that in a first step the tartaric acid pellets are produced by powder layering, which are sprayed in a second step with an ethanolic isolation suspension which comprises hydroxypropylmethyl cellulose (HPMC).
WO2009/118322 describes a process characterized by a series of partial steps. First, the core is produced from a pharmaceutically acceptable organic acid, preferably tartaric acid by powder layering. The cores are then converted into so-called isolated tartaric acid cores by spraying on an isolating suspension. A dabigatran etexilate suspension prepared subsequently is sprayed onto these coated cores in one or more process steps by means of a coating process. Dabigatran etexilate methanesulfonate, as polymorph I, is suspended together with talc and hydroxypropylcellulose in isopropanol (isopropyl alcohol, 2-propanol, 2-PrOH), the preparation of the suspension being carried out at a temperature not exceeding 30[deg.] C. Finally, the active substance pellets thus obtained are packed into suitable capsules.
In WO2010/007016 the process disclosed in WO2009/118322 is further characterized by that polymorph I of dabigatran etexilate methanesulfonate being characterised by a melting point of Tmp.=180+-3[deg.] C. as determined by DSC at a heating rate: of 10[deg.] C./min) is suspended together with talc and hydroxypropylcellulose in isopropyl alcohol, the preparation of the suspension being carried out at a temperature not exceeding 30[deg.] C. by the circulatory dispersal process.
The formulations described in the above patents and/or patent applications contain a tartaric acid crystal core, which increases the dissolution rate of dabigatran by modifying the pH of the microenvironment when the pellet is dissolved. On the other hand, dabigatran etexilate is unstable in the presence of tartaric acid; therefore, an isolating layer between the tartaric acid core and API (Active Pharmaceutical Ingredient) layer has to be applied. This is particularly tricky since the tartaric acid cores are produced by powder layering of tartaric acid dust onto tartaric acid crystals. The cores produced by such a process are only quasi-spherical and it is very difficult to avoid the formation of satellites which cause defects in the isolating layer. The so-called satellites are small particles adhering to the outside of the otherwise rounded pellets and detracting from the otherwise spherical geometry of the pellets. These lead to

impaired storage stability and hence durability of the finished product. Furthermore, protection from humidity during manufacture and storage to prevent hydrolysis of the prodrug forming moieties and polymorphic form transformations, is recommended. Also, HPMC capsule shells and expensive packaging materials are necessary to assure adequate stability of the final product.
Further on, the technological process described in WO03/074056, WO2009/118321, WO2009/118322, and WO2010/007016 is in all cases powder layering, which is a very complicated and long process, as the tartaric acid crystals of 0.4-0.6 mm size are portionwise and altemately-up to 300 times-sprayed with a solution of acacia and tartaric acid in water, and coated with fine tartaric acid dust with particle size of up to 100 micrometers, preferably below 50 micrometers. It is also complicated to control the particle size of the tartaric acid crystals used as cores as well as the particle size of the tartaric acid dust. The surface of the so called starter pellets (i.e. tartaric acid crystals alternately coated with an aqueous solution of tartaric acid/acacia (acting as »glue«) and a layer of fine tartaric acid dust) can be rough and have an increased surface area, and in some cases may also not be sufficiently firm for further processing.
US2003/0181488Aldescribesan oral formulation of dabigatran etexilate, which purport to provide pH-independent bioavailability of the active agent. The formulations contain a pharmaceutically acceptable organic acid having a water solubility of more than 1 g/250 ml at 20°C. The dosage forms are multi-particulate compositions containing pellets prepared by coating tartaric acid crystals of a specific particle size with a solution of tartaric acid dissolved in gum arabic. The coated crystals are sprinkled with powdered tartaric acid prior to screening to a specific size.
WO2005/018615 describes tablets comprising dabigatran etexilate and containing 5 wt. % to 50 wt. % of the active substance (based on the methanesulphonate), 5 wt. % to 50 wt. % of a pharmaceutically acceptable organic acid with a solubility in water of >1 g/250 mL at 20°C as well as other excipients and fillers.
WO2005/023249 describes a pharmaceutical composition comprising: dabigatran etexilate or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable lipophilic liquid, solid, or semi-solid carrier system.

WO2012001156A2 describes a process for the preparation of starter pellets, characterized in that a neutral core, chosen from the group of sucrose, microcrystalline cellulose, starch, or a tartaric acid core is coated with a solution of tartaric acid and optionally a binder and/or further inert pharmaceutical excipients without powder layering with tartaric acid.
US20120301541 describes the compressed cores which can be used for pharmaceuticalcompositions and dosage forms. The compressed cores of the present invention contain an organic acid, and are particularly useful for the preparation of pharmaceutical compositions containing a drug in which dissolution of the drug is favored in acidic environments.
US2013177652A1 describes asolid oral dosage form of dabigatran etexilate methanesulfonate. It is produced by suspension/solution layering of tartaric acid onto spherical cores, such as neutral cores comprised of sucrose, microcrystalline cellulose and starch, or tartaric acid pellets, followed by an isolating layer and the layer comprising the active pharmaceutical ingredient. Optionally, an overcoat can be applied.
Based on the above one can conclude that there is a need for improved pharmaceutical formulation of Dabigatran etexile methyl sulfonate and it's pharmaceutically acceptable salts thereof, preferably dabigatran etexilate methanesulfonate.lt is known that the solubility of weakly basic drugs, such as dabigatran and dabigatran etexilate, may be increased by the provision of an acidic environment. Hence, the provision of an acidic medium at the intended site of drug release can increase the release rate from the dosage from. In addition this, there is a further need to provide simplified and more cost effective processes for the preparation of the dosages forms of such drugs. The present invention deal with this need and prepared the pharmaceutical formulation comprised of preparing Dabigatranetexile methyl sulfonate pellets and tartaric acid pellets, separately followed by filling of both the pellets into the Hard gelatin or HPMCcapsule with or without carrageenan.
In another object of invention, it is surprisingly found that an HPMC capsule containing two distinct units i.e. drug substance pellets which is prepared by using inert spheresand there by inert coating. The second component, acidic pellets separately prepared. These two separate units are filled into the HPMC or HG capsules. These units can be prepared by various methods known to prior art like, extrusion, spheronization, pellatization by layering and or by

conventional technique . This process of encapsulation of HPMC or hardgelatin capsules can be done on manual, semi-automatic and automatic machines.
The problem to be solved by the present invention was therefore to provide an improved formulation method for the production of a pharmaceutical containing dabigatranetexilate and also for its pharmaceutically acceptable salts thereof, in which the aforementioned disadvantages and in particular.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a pharmaceutical formulation of dabigatranetexilate and its pharmaceutically acceptable salts thereof and process for the preparing thereof, preferably dabigatranetexilatemethanesulfonate, and/or improved, more cost effective processes and simplified technological processes for the production thereof
It is also an object of the present invention to provide a pharmaceutical formulation comprising of Dabigatranetexile methyl sulfonate pellets which are prepared with the aid of solvents and sprayed on to the inert spheres.
It is also an object of the present invention to provide a pharmaceutical formulation comprising Dabigatran etexilate methyl sulfonate pellets and tartaric acid pellets followed by filling of both the pellets into the HPMC capsule with or without carrageenan.
The pellets manufactured preferably comprising the pharmaceutically suitable excipients such as but not limited to diluents, disintigrant, and lubricant with organic acids substance and compressing all these excipients into the pellets.
The present invention relates in a preferred embodiment to an improved pharmaceutical formulation comprising dabigatranetexilate and its pharmaceutically acceptable salts thereof, in particular dabigatranetexilatemethanesulfonate, and the process for its preparation.
In another object of innovation, it is surprisingly found that an HPMCor HG capsule containing two distinct parts of Drug substance pellets and organic acid substance pellets. These two separate pellets are prepared separately and filled into the HPMCor HGcapsules. These pellets can be prepared by various methods known to prior art like, extrusion, spheronization, penalization by layering and or by compressing. This process of

encapsulation of HPMCorHGcapsulescan be done on manual, semi-automatic and automatic
machines.
Accordingly, it is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.
SUMMARY OF THE INVENTION
In one aspect, the present invention providesa pharmaceutical formulation of dabigatranetexilate and its pharmaceutically acceptable salts thereof and process for the preparing thereof, preferably dabigatranetexilatemethanesulfonate, and/or improved, more cost effective processes and simplified technological processes for the production thereof.
In another aspect of the present invention providesa pharmaceutical formulation comprising of Dabigatranetexile methyl sulfonate pellets which are prepared with the aid of solvents and sprayed on to the inert spheres.
Yet, another aspect of the present invention provides a pharmaceutical formulation comprising Dabigatran etexilate methyl sulfonate pellets and tartaric acid pellets followed by filling of both the pellets into the HPMC capsule with or without carrageenan.
The pellets are manufactured preferably comprising the pharmaceutically suitable excipients such as but not limited to diluents, disintigrant, and lubricant with organic acids substance and compressing all these excipients into the pellets.
The present invention relates in a preferred embodiment to an improved pharmaceutical formulation comprising dabigatranetexilate and its pharmaceutically acceptable salts thereof, in particular dabigatranetexilatemethanesuJfonate, and the process for its preparation.
In another object of innovation, it is surprisingly found that an HPMCor HG capsule containing two distinct parts of Drug substance pellets and organic acid substance pellets. These two separate pellets are prepared separately and filled into the HPMCor HGcapsules. These pellets can be prepared by various methods known to prior art like, extrusion, spheronization, pellatization by layering and or by compressing. This process of encapsulation of HPMCor HGcapsules can be done on manual, semi-automatic and automatic machines.

DETAILED DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
The term "composition" or "formulation" has been employed interchangeably for the purpose of the present invention.
The term "dosage form" is as used herein is intended to mean a pharmaceutical composition which is suitable for administration to a patient. In one embodiment the compositions of the present invention can be in the form of capsules, tablets, minitablets, stick formulation, dispersible tablets, dry suspension for reconstitution, powder or granule for solution or suspension, granules, and the like or any combinations thereof. Depending of the final dosage form the compositions of the present invention may comprise appropriate pharmaceutical^ acceptable excipients such as those mentioned above or some additional ones such as, but not limited to, sweeteners, flavors, colorants and the like or combinations thereof. Further it is contemplated within the scope of the invention that the dosage form can be encapsulated or coated. In one embodiment, the composition of the present invention is in the form of a capsule. Capsules include, for example, hard capsules of gelatine or hydroxypropylmethylcellulose and the like. In a further embodiment, the compositions of the present invention may be manufactured using conventional techniques known in the art.
For purposes of the invention disclosed and claimed herein, the following terms and abbreviations have the following meanings.
The term "treatment" is defined to include preventing, lowering, stopping, or reversing the progression or severity of a condition or symptom being treated. As such, the present invention includes both medical therapeutic and/or prophylactic administration, as appropriate.
The term "salt" refers one or more molecules of a salt associated with a molecule of a compound, such as the compound of structural formula (I) associated with a molecule of water or acetic acid. The term "pharmaceutically acceptable salt" refers to those salts which are, according to medical judgement, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art.

The term "organic acid"refers one or more pharmaceutically acceptable organic acid which is selected from the group consisting of fumaric acid, tartaric acid, citric acid, succinic acid, adipic acid, malic acid, maleic acid, lactic acid, or a mixture of one or more thereof.
The term "inert core" refers to the core material produced by sugar, mixture of starch and sugar, cellulose like MCC etc, syloid etc.
The term "binder"refers suitable binders for the subcoat layer include cellulosic polymers such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, gelatin, methyl cellulose, pregelatinized starch, acacia, alginic acid, sodium carboxymethyl cellulose gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, and copolymers of N-vinyl pyrrolidine and vinyl acetate, or a mixture thereof. Of these, the cellulosic polymers, e.g. hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose and methyl cellulose are preferred. Hydroxypropylmethyl cellulose (e.g. HPMC 2910), hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose or mixtures thereof, are particularly preferred binders for the subcoat layer. Preferably the binders for the subcoat are hydroxypropylmethyl cellulose or ethyl cellulose or a combination thereof.
The term "diluent" refers to compounds typically used in the formulation of pharmaceuticals to impart bulk for the manufacture of a tablet of practical size. Diluents include water soluble and insolubles listed in the hand book of excipients.The term "diluent" or "filler" as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Examples of suitable diluents include, but are not limited to microcrystalline cellulose, coprocessed microcrystalline celluloses (such as Avicel C1-611, Avicel RC-581 ,Avicel RC591 , Avicel CE, Avicel DG, Avicel HFE), lactose, sucrose, xylitol, mannitol, maltose, polyols, fructose, guar gum, sorbitol, magnesium hydroxide, dibasic calcium phosphate, kaolin, calcium sulphate, carrageenan, chitosan, pectinic acid, sodium alginate, magnesium aluminium silicate, calcium carbonate and the like, combinations thereof and other such materials known to those of ordinary skill in the art.
The term "disintegrant" refers any agent which facilitates the disintegration of the dosage form. Many examples of the disintegrating agents are listed in the hand book of excipeints.

The term "wetting agent" or "surfactant" refers to anionic, cationic, and nonionic surfactants. Nonlimiting, representative wetting agents include sodium lauryl sulfate, docusate sodium (i.e., bis(2-ethyl-hexyl)sodium sulfosuccinate), ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides and ethoxylated derivatives thereof, and diglycerides and ethoxylated derivatives thereof. Preferably the surfactant is sodium lauryl sulfate or a polyoxyethylenesorbitan fatty acid ester, particularly polysorbate 80.
The term "lubricant" refers to pharmaceutically acceptable agents that are commonly used in the art as lubricants or glidants in the preparation of solid pharmaceutical formulations. Representative lubricants include, but are not limited to, agents such as talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, calcium silicate, a starch, mineral oil, a wax, glycerylbehenate, a polyethylene glycol, sodium benzoate, sodium acetate, sodium stearylfumarate, and hydrogenated vegetable oils. Preferably, the lubricant is selected from the group consisting of magnesium stearate, sodium stearylfumarate, and stearic acid.
Therefore, the instant pharmaceutical composition in bulk and capsulecontaining Dabigatranetexile methyl sulfonatepellets and tartaric pellets, both the pellets either seal coated or uncoated.Dabigatranetexilate methyl sulfonate pellets prepared using microcrystalline cellulose spheres. Initially Dabigatranetexilate methyl sulfonate dissolved into solvents and sprayed on to the microcrystalline cellulose spheres. The above prepared drug pellets are seal coated using polymers like hydroxyl ethyl cellulose, hydroxyl propyl cellulose and or Hypromellose.Tartaric acid pellets are seal coated using Hypromellose and dimethicone dissolving in to purified water and Isopropyl alcohol.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.

Example 1 Manufacturing of Pellets A:

Sr.No Ingredients mg/Capsule
Drug loading Stage
1. Sugar Spheres 150.00
2. Dabigatranetexilatemesylate 173.00
3. Hydroxy propyl cellulose (Klucel - EF) 8.00
4. Colloidal silicon dioxide (Aerosil) 1.67
5. Isopropyl alcohol qs
Total drug loaded spheres weight 332.67
Seal coating stage
6. Drug loaded pellets 332.67
7. Hydroxy propyl cellulose (Klucel - EF) 1.00
8. Isopropyl alcohol qs
Total seal coated drug loaded spheres weight 333.67
Manufacturing of Pellets B:

Sr.No Ingredients mg/Capsule
Seal coating of tartaric acid pellets
1. Tartaric Acid pellets 177.12
2. Hypromellose (Methocel E5 Premium LV) 10.00
3. Dimethicone 0.05
4. Talc (micronized) 1.12
5. Ethanol qs
6. Purified water qs
Total seal coated tartaric acid pellets weight 182.78
Filling of Pellets A & B into Hard gelatin / HPMC Capsule:

Sr.No Ingredients mg/Capsule
1. Seal coated drug loaded spheres 333.67
2. Seal coated tartaric acid pellets 182.78
Total fill weight of capsule 516.45

Example 2 Manufacturing of Pellets A:

Sr.No Ingredients mg/Capsule
Drug loading Stage
1. MCC spheres 150.00
2. Dabigatranetexilatemesylate 173.00
3. Hydroxy propyl cellulose (Klucel - EF) 9.67
5. Ethanol qs
Total drug loaded spheres weight 332.67
Seal coating stage
6. Drug loaded pellets 332.67
7. Hydroxy propyl cellulose (Klucel - EF) 5.00
8. Isopropyl alcohol Qs
Total seal coated drug loaded spheres weight 337.67
Manufacturing of Pellets B:

Sr.No Ingredients mg/Capsule
Seal coating of tartaric acid pellets
1. Tartaric Acid pellets 177.12
2. Hypromellose (Methocel E5 Premium LV) 20.00
3. Dimethicone 0.05
4. Talc (micronized) 1.12
5. Ethanol qs
6. Purified water qs
Total seal coated tartaric acid pellets weight 192.78
Filling of Pellets A & B into Hard gelatin HPMC Capsule:

Sr.No Ingredients mg/Capsule
1. Seal coated drug loaded spheres 337.67
2. Seal coated tartaric acid pellets 189.78
Total fil 1 weight of capsule 516.45

Claims:
1. A pharmaceutical composition comprising a) Dabigatranetexile methyl sulfonate pellets without talc and b) Organic acid pellets.
2. The pharmaceutical compositionaccording to claim 1, comprising

a) preparing Dabigatranetexile methyl sulfonate pellets by drug loading on microcrystalline spheres or sugar spheres or any conventional spheres.
b) preparing tartaric acid pellets by coating polymer on tartaric acid pellets.

3. The pharmaceutical compositionaccording to claim 1, wherein the pellets filling into Hardgelatin Capsules or HPMC Capsules with or without carrageenan.
4. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable organic acid is selected from the group consisting of fumaric acid, tartaric acid, citric acid, succinic acid, adipic acid, malic acid, maleic acid, lactic acid, or a mixture of one or more thereof.
5. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable organic acid is tartaric acid.