WO2003077829A2

WO2003077829A2 - Process for preparation of a pharmaceutical composition containing acid labile compounds

Info

Publication number: WO2003077829A2
Application number: PCT/IB2003/000827
Authority: WO
Inventors: Bakulesh Mafatlal Khamar
Original assignee: Modi, Rajiv, Indravadan; Dave, Brijesh; Ramani, Chandia, Chimandas; Naik, Praful
Priority date: 2002-03-08
Filing date: 2003-03-06
Publication date: 2003-09-25
Also published as: KR20050008452A; GB2392839A8; AU2003208505A1; AU2003209534A1; AU2003208505A8; AU2003209534A8; WO2003075825A2; WO2003077829A3; GB2392839A; GB0400094D0; WO2003075825A3

Abstract

Process for preparation of a pharmaceutical formulation containing an acid unstable compound together with an alkaline reacting substance as core material , one or more subcoating layer(s) and an enteric coating .

Description

PROCESS FOR PREPARATION OF PHARMACEUTICAL COMPOSITION

The present invention provides a process for preparation of a oral pharmaceutical composition of an acid labile drugs like benzimidazole derivatives which are also know as protein pump inhibitors these compounds are ordinarily not very stable and needs special coating as well as packaging and storage condition. The present invention provides the process for manufacturing pharmaceutical composition in such a way that the product is stable and special packaging as well as storage requirement are obviated. The process comprises of proving three different layers over a coat containing acid labile drug. All the three coats have different coating agents. The product so manufactured is characterized by a) core containing acid labile drug, b) sub coat, a separating layer, c) seal coat is a layer which separate the sub coat with enteric coat. The seal coat is consisting of water insoluble but water permeable material like hydroxy propyl methyl cellulose 15 cps, ethyl cellulose, and cellulose acetate phthalate. andd) The enteric coating layer.

This composition offers distinct advantages. It is a unique composition with regards to providing a protection against humidity or external environment to the acid labile drugs in the core. It also gives the better disintegration time profile. Moreover, this formulation does not require any special packaging or storage conditions.

Prior Art: .

Acid sensitive drugs, such as anti-ulceratives, antibiotics proteins and protonpump inhibitors like benzimidazole, which are inactivated in the stomach by low pH media have to be protected with enteric coatings. The polymers which are used for such purposes contain itself acid carboxylic groups, and interactions with the drugs during the coating process or storage alters the product anddisturbs the stability. In order to avoid interactions between the drug and the polymer, another coating with a neutral polymer as a pre coat is used. In certain cases it might be helpful to add slightly alkaline substances to the tablet formulation i order to keep the pH-value nearly neutral.

Benzimidazole derivatives having an IΪ-K⁺ ATPase inhibition effect, which are useful in the treatment of digestive ulcers, since they would intensely suppress the secretion of gastric acid. They are also known as Proton pump inhibitors. Proton pimp inhibitors are benzimidazoles derivatives like Omeprazole, Lansoprazole, Rabaprazole etc. Since these compounds exert, intense and persistent effects, they attract public attention as novel drugs for treating digestive ulcers which substitute for histamine preceptor antagonists such as cimetidine. Animal tests have indicated that 2[{4~(3-methoxypropoxy)3- methylpyridin-2-yl}methylsulfinyl}lH-benzimidazole sodium, among these compounds, has a particularly intense effect of suppressing gastric acid secretion and an appropriate duration of the action. Thus it is expected to be clinically useful.

However the above mentioned benzimidazole derivatives are poor in stability. In particular, they would be rapidly decomposed aύ colored under moist conditions or in an acidic to neutral aqueous solution. When these compounds are to be formulated into a preparation for oral administration, therefore, it should be coated with an enteric coating to thereby prevent the decompositionof the same with gastric acid. However an enteric coating is an acidic material, which is insoluble in water under acidic conditions and soluble in water under neutral to alkaline conditions. Thus the coating of a core comprising an acid-labile compound, e.g., a benzimidazole derivative with such an enteric coating might generally cause the decomposition of said acMabile compound. Such decomposition occurs even during the enteric coating stage by a common method, for example, with the use of a fluidizedbed coater, which results in the coloration of the surface of the core. Further the storage stability of the coated core as well as the stability in an acidic solution of the same might be lowered thereby.

In order to avoid these difficulties, Japanese Btent No. 258316/1987 and No. 258320/1987 disclose each a method comprising inteπnediately coating the core containing an acid4abile compound with a material soluble in water or decomposable in water and then further coating the same with an enteric coating. However these methods cannot sufficiently stabilize an acidlabile compound and therefore further improvement is required.

Several patents discloses the various materials to be used as a separating layer between core and enteric coating layer. US patent nos. 4853230, 4871734, 5035899, 5626875, 5385739, 6228400B1, 6013281, 6159499, 6207198, and 6248355 discloses the separating layer between core and enteric coating layer while formulating Benzimidazole free base or alkaline salts thereof. The intermediate layer or subcoat layer is made up of water soluble or slightly water soluble film forming materials with or without alkaline compounds. Enteric coating layer is described in above mentioned patents are Hydroxypropylmethylcellulose phthalate, copolyme-sed methacrylic acid and its esters, Cellulose acetate phthalate, and polyvinyl phthalate. The core containing acid labile proton pump inhibitors either as a free base or an alkaline salts of the compound with or without alkaline reacting substance.

US pat. No. 4,853,230 describes the such enteric coated preparations of acid labile substances. Said preparation contains an alkaline core material comprising the active substance, a separating layer and the enteric coating layer.

US Pat. No. 5035899 discloses a peroral preparation of acid unstable compound characterized in that a core containing an acid unstable compound is coated with a slightly water soluble film forming material, and further coated with an enteric coating. However, this method cannot sufficiently stabilize acid labile drugs with respect to degradation due to moisture

US Pat No. 6013281 describes a method of making a pharmaceutical dosage form containing proton pump inhibitors. This invention is characterized by the presence of a separating layer between an alkaline reacting core material comprising a pharmaceutically active acid labile substance and an enteric coating layer, wherein the separating layer comprises a water soluble salt of an enteric coating polymer. However, this formulation may require special packaging to protect the formulation from the external environment.

However, these methods cannot sufficiently stabilize acid labile drugs with respect to degradation due to environmental condition. It is also not possible to providedfmulation using these processes to have necessary disintegration time for the formulation. These formulations also required special packaging to protect the formulation from the external environment.

We have tried to leproduce the described methods of subcoating and enteric coating to formulate the pharmaceutical composition benzimidazole derivatives(Rabaprazole sodium) containing with or without alkaline reacting substance.

Following is the details of the experiments performed. None of these experiments provided a stable product.

Experiments 1 : Core- sub coat with HPMC- Enteric coating with CAP Experiments 2: Core- sub coat with HPMC- Enteric coating with CAP Experiments 3: Core- sub coat with HPMC Phthalate- Enteric coating with Eudragit L 30D Experiments 4: Core- sub coat with calcium carbonate and PNP- Enteric coating with

Eudragit L 30D Experiments 5: Core- sub coat with PNC- Enteric coating with HPMC Phthalate

The ingredients, used in above experiment are summaries in table one which is summarized in Table: 1. In all the Experiments the active material did not remain stable. Therefore there is a need to develop a new coating method to provide the stability to acid labile substances. Table: 1

The objective of present invention is to provide a novel process for preparation of pharmaceutical composition containing acid labile and moisture sensitive drugs like Omeprazole, rabeprazole, Lansoprazole, pentaprazole, etc.

The further objective of presert invention is to provide process for manufacturing pharmaceutical compositions containing acid labile^' and moisture sensitive drugs like omeprazole, rabeprazole, lansoprazole, pentaprazole, etc. so that they remain stable over a prolonged period.

The further objective of present invention is to provide process for manufacturing pharmaceutical compositions containing acid labile and moisture sensitive drugs like omeprazole, rabeprazole, lansoprazole, pentaprazole, etc. so that their dissolution time is within prescribed limit.

The further objective of present invention is to provide process for manufacturing pharmaceutical compositions containing acid labile and moisture sensitive drugs like omeprazole, rabeprazole, lansoprazole, pentaprazole, etc. so that, storage conditions is minimized.

The further objective of present invention is to provide process for manufacturing pharmaceutical compositions containing acid labile and moisture sensitive drugs like omeprazole, rabeprazole, lansoprazole, pentaprazole,etc. so that the special packaging requirements are minimized.

Detailed description of the invention:

In the present invention, the extensive studies have been conducted in order to further stabilize an acid-labile compound contained in a core. As a result, it has been found that the conventional methods can be improved by providing a separate intermediate layer (seal coat) between subcoat and enteric coat. According to present invention core can be in the form of particle granules of a tablet. This core may, may not contain alkaline substances. The active ingredient into core may be alkaline salt or any other salt. The core is coated with coating material using organic solvents(sub coat). The coating material used for sub coat are polymers which are preferably water soluble. It is covered by another intermediate coating(seal coat) using organic solvents. The coating agents used for this coat are mixture of more than one coating substances selected from group of water soluble, water insoluble or slightl ater soluble coating agents. The final coating is provided using enteric coating substances. Pharmaceutical composition made as per present invention are found to be stable under all conditions of testing. They does not need any special packaging material or storage condition to maintain stability. In spite of the fact that three layers are applied the disintegration time and dissolution profile is not affected. The bioavailability of the product is also maintain.

The present invention can be described based on the following examples.

Example I. Process of manufacturing of a pharmaceutical preparation:

As per present invention process for manufacturing pharmaceutical compositions containing acid labile substances comprises steps of manufacturing a as containing active substance, which is coated by three consecutive different layers of coating, the last external of which is enteric coating. The first layer immediately in vicinity of core is labeled as sub coat and intermediate coated layer is calledvs seal coat.

a) Preparation of core:

The core can be in the form of tablet, granules or particles.

i) tablet is compressed by blending active pharmaceutical substances with excipients with or without alkaline reacting material. ii) Granules can be piepared in an identical way.

iii) The core may also be prepared by coating inert core with active pharmaceutical substances.

A typical example of process for preparation of tablet is described as under:

The core is prepared by mixing the acid labilesubstance with pharmaceutical excipients like mannitol, microcrystalline cellulose, and starch and with or without alkaline reacting material. The mixture was granulated with hydroxy propyl cellulose, dried and passed through 20 mesh sieve to give granule. Separately carboxymethyl cellulose was mixed with magnesium stearate and tare were added in the granules. The granules and CMC, talc and magnesium stearate were mixed together and compressed into a tablet with a double rotary tablet machine.

b) Sub coating

Sub coating as per present invention can be applied with any coating material. It may or may not contain alkaline substances. However, it is necessary that its pH should be neutral or alkaline. It is preferable to avoid use of water as solvent durig the process. It is preferable to use water soluble polymers as coating substance.

The solution for subcoating layer is prepared by dissolving hydroxypropyl methyl cellulose and propylene glycol in isopropyl alcohol and methylene chloride. The magnesium chloride is also dispersed in this solution. Coating of this dispersion is given to core tablet or granules with a coating pan speed of 812 rpm, spray rate of 758/gun/minute. The inlet temperature should be 30°C and relative humidity of not more than 40%. The speed of peristaltic pump is 1520 rpm and the rate of compressed air is 3.5 -4 kg/cm sq.

c) Intermediate layer (Seal coat): The intermediate layer (seal coat) is provided with a mixture of coating substances in organic solvent. The polymer for coating are selected from group of water soluble as well as water insoluble coating agents.

Seal coat is applied over a sub coat. The solution for seal coat layer is prepared by dissolving polymers like hydroxypropyl methyl cellulose, ethyl cellulose and cellulose acetate phthalate in isopropyl alcohol and methylene chloride. Coating of this mixture of polymers is given over sub coat. The ratio of these material is 24:67:9 with each other respectively for Hydroxy propylmethylcellulose, cellulose acetate phti-iate and ethylcellulose. The concentration used is not less than 0.05% and not more than 2% of the polymers as compared to the total weight of tablet.

d) Enteric coat:

Then the core thus coated with the seal coat coating layer is further coated with an enteric coating to thereby give a stabilized peroral preparation of an acid-abile compound according to the present invention. The coating with an enteric coating may be carried out in a conventional manner. Namely, the enteric material is dissolved or suspended in a solvent optionally together with a plasticizer, and the solution thus obtained is applied onto the secondly coated core in a conventional manner. Example II. Examples of materials a) Acid-labile substance Proton pump inhibitors like-

Omeprazole

Rabeprazole

Pantoprazole

Lansoprazole

b) Alkaline reacting substances

Magnesium oxide Sililic anhydride Calcium silicate Magnesium hydroxide Magnesium carbonate Aluminium hydroxide Calcium stearate Magnesium stearate

c) Sub coating polymers

Hydroxy propyl methyl cellulose Microcrystalline. cellulose Hydroxy ethyl cellulose Hydroxy methyl cellulose Polyvinyl pyrrolidone dextran

d) Seal coat polymers

• hydroxy propyl methyl cellulose

• Ethyl cellulose

• Cellulose acetate phthalate

e) Enteric coating polymers

• Hydroxy propyl methyl cellulose phthalate • Copolymers of methacrylic acid and methyl methalrycate

• Polyvinyl acetate phthalate

Example III. Thickness of the pharmaceutical preparation:

The tablet thus prepared based on the process of the present invention the thickness of the each coat is described as follows.

a) Sub coat : 0.01 to 0.15 mm b) Seal coat : 0.02 to 0.3 mm c) Enteric coat : 0.03 to 0.6 mm

Example IV. Disintegration and Dissolution Properties:

Disintegration : The disintegration of the tablet under standard conditions for core, seal coated tablets and enteric coated tablets are as per follows, i. Core : 4-7 min ii. Seal coated tablet : 8-10 min iii. Enteric coated tablet : Do not disintegrate in 0.1N HC1 for 2 hrs and disintegrate within 30 min at pH 7.2

Dissolution : The dissolution of the preparations obtained as per the present invention is as follows. i. In 0.1 N HC1 for 2 hours : Should not bemore than 15% and more preferably not more than 7%. ii. pH 6.8 buffer for 1 hour : Should not be less than 70% and more preferably not less than 80%. Example V. Stability

a. Pharmaceutical compositions prepared according to present invention are found to be stable at standard conditions as well as accelerated testing conditions. b. Pharmaceutical compositions prepared as per present invention remains stable at all testing condition even in ordinary packing. It is not necessary to store/pack a productin moisture proof container. c. Pharmaceutical compositions made as per present invention are found to be stable at room temperature in absence packing or special container. d. Pharmaceuticals compositions made as per present invention are found to be stable at room temperature when they are exposed to usual environmental condition.

Example NI. Proportion of various layers in a pharmaceutical preparations:

According to the present invention for a process for manufacturing pharmaceutical preparations, the proportion of a various layers is found to be as follows.

Core : 70% to 90% Sub coat : l% to 7% Seal coat : 0.5% to 5% Enteric coat : 5% to 20%

To further illustrate the present invention, the following Examples will be given,

EXAMPLE A The acid labile substance, mannitol, microcrystalline cellulose and magnesium oxide were mixed together. To the obtained mixture was added hydroxypropylcellulose dissolved in special denatured spirit. The mixture was granulated, dried and passed through a 20-mesh sieve to give granules. Separately carboxy methyl cellulose was mixed with magnesium stearate and purified talc were added thereto. The granules and carboxymethyl cellulose, talc and magnesium stearate were mixed together and compressed with a double rotary tablet machine. Thus uncoated tablets of the following composition each weighing 266 mg were obtained. The thickness of the core tablet is found to be 3.65mm.

Composition:

Rabeprazole sodium 20 mg mannitol 90 mg magnesium oxide 80 mg hydroxypropylcellulose

5 mg Microcrystalline cellulose 20 mg starch 20 mg carboxymethylcellulose calcium

20 mg talc 4 mg magnesium stearate 5 mg

1.683 kg of hydroxypropylmethyl cellulose and 163 g of propylene glycol were dissolved in 17.5 liter Isopropyl alcohol and 17,5 liter of methylene chloride and 163 g of magnesium chloride was dispersed in the obtained solution. The uncoated tablets obtained above were intermediately coated with the dispersion thus obtained by conventional coating methods. Thus sub coated tablets each weighing 271.25 mg were obtained. The thickness of the sub coat for this example is 0.05mm. 572 g of hydroxypropylmethyl cdlulose, 211 g of ethyl cellulose and a.595 kg of cellulose acetate phthalate dissolved in 29.0 liter of isopropyl alcohol. The sub coated tablet obtained above were coated with this polymer solution to get seal coat layer. Thus seal coated tablets each weighing 276.66 mg were obtained. The thickness of the seal coat for this example is 0.1mm.

Next, 7.818 kg of hydroxvpropylmethylcellulose phthalate, 1.562 of titanium oxide, 0.778 kg of talc and 1.170 kg of a dibutyl phthalate were dissolved and/or dispersed in a mixture of 50% isopropyl alcohol with methylene chloride. The abovdescribed tablets were coated with the solution thus obtained in conventional coating pan. Thus enteric tablets each weighing 304.63 mg were obtained. The thickness of the entericoat for this example is 0.2mm.

The disintegration of the final formulation obtained according to above example is as follows.

Core tablet : 4 min

Core with seal coat : 9 min

Core with enteric coat : 10 min

The dissolution of the final formulation obtained according to above example is as follows.

In 0.1 N HC1 for 2 hours : 5% In pH 6.8 buffer for 1 Hour : 85%

EXAMPLE B

When the coating sequence has changed, the product does not remain stable. When core is coated immediately with the seal coat first aid then sub coat as describe in example I above and then with enteric coat. It is observed that the product does not remain stable. A typical example has been shown as follows.

Claims

1. A process for preparation of a pharmaceutical composition for oral use with desired dissolution profile and stability comprises steps of manufacturing a) a core containing a pharmacologically effective acid labilesompound. and/or its alkaline salts,optionally with alkaline reacting substance. b) An inert subcoating layer which isa first coating layer, coated on the core, comprising film forming materialssuch as hydroxypropylmethyl cellulose, microcryslline cellulose, polyvinylpyrrolidone, hydroxymethylcellulose, hydroxyethylcellulose, dextran and optionally water insoluble particles such as magnesium oxide, sililic anhydride, calcium silicate, magnesium hydroxide, magnesium carbonate, aluminium hydroxide, calcium stearate and magnesium stearate. c) Second coat, termed as a seal coat, comprising of a mixture of polymers like hydroxypropylmethyl cellulose, cellulose acetate phthalate, and ethyl cellulose overthe subcoat. d) An enteric coating layer surrounding said seal coat layer, wherein the seal coat layer isolates the core andthe subcoat layer from the enteric coating layer.

2. A process for preparation of stable oral pharmaceutical composition as claimed in claim 1, in which acid labile compound is benzimidazole compound.

3. A process for preparation of a pharmaceutical composition as claimed in claims 1 and 2, in which benzimidazole compound is preferably a proton pump inhibitors like rabeprazole omeprazole, lansoprazole, and pantaprazole and alkaline salts thereof.

4. A process for preparation of a pharrmceutical composition as claimed in claim 1, in which a water insolubleparticles for subcoating is having particle size less than 40 mesh

5. A process for preparation of a pharmaceutical composition as claimed in claims 1, in which the concentrationof hydroxypropylmethyl cellulose is in the range of 0.1% to 0.75% of total weight.

6. A process for preparation of a pharmaceutical composition as claimed in claims 1 and 5, in which the concentration of hydroxypropylmethyl cellulose is more preferably in the range of 0.3% to 0.6% of total weight.

7. A process for preparation of a pharmaceutical composition as claimed in claims 1, in which the concentration of ethyl cellulose is in the range of 0.05% to 0.5% of total weight.

8. A process for preparation of a pharmaceutical composition as claimed in claims 1, and 7, in which the concentration of ethyl cellulose in a second coat, seal coat is preferably in the range of 0.1% to 0.4% of total weight.

9. A process for preparation of a pharmaceutical composfiion as claimed in claims 1, in which the concentration of cellulose acetate phthalate in a second coat, seal coat is in the range of 0.15% to 2.0% of total weight.

10. A process for preparation of a pharmaceutical composition as claimed in claims 1 and 10, in which the concentration of cellulose acetate phthalate is more preferably in the range of 0.9%) to 1.6% of total weight.

11. A process for preparation of a pharmaceutical composition as claimed in claim 1 , in which the enteric coating layer comprisingof a material selected from hydroxypropylmethyl cellulose phthalate, copolymers of methacrylic acid and methyl methacrylate, dibutyl phthalate and polyvinyl acetate phthalate.

12. A process for preparation of a pharmaceutical composition as claimed in claim 1, in which the thickness of subcoat layer is in the range of 0.01 mm to 0.15 mm.

13. A process for preparation of a pharmaceutical composition as claimed in claim 1, in which the thickness of seal coat layer is in the range of 0.02 mm to 0.3 mm.

14. A process for preparation of a pharmaceutical composition as claimed in claim 1, in which the thickness of enteric coat layer is in the range of 0.03 mm to 0.6 mm.

15. A process for preparation of a pharmaceutical composition as claimed in claims 1 to 14 provides a pharmaceutical preparation containing acid labile substance which is stable .

16. A process for preparation of a pharmaceutical composition as claimed in claims 1 to 15 provides a pharmaceutical preparation containing acid labile substance which is stable even when packed in ordinary packing material.

17. A process for preparation of a pharmaceutical composition as claimed in claims 1 to 16 provides a pharmaceutical preparation containing acid labile substance which is stable even when expos to environment at room temperature without packing.

18. A process for preparation of a pharmaceutical composition as claimed in claims 1 and 17 in which dissolution of the stable oral pharmaceutical preparation is not more than 15% in 0.1N Hydrochloricacid and not less than 70% in pH 6.8 buffer.