WO2021234724A1

WO2021234724A1 - Pharmaceutical formulation containing stable granules of clavulanic acid

Info

Publication number: WO2021234724A1
Application number: PCT/IN2021/050415
Authority: WO
Inventors: Vengandur Srikumar RAGHUNATHAN
Original assignee: Twenty First Century Pharmaceuticals Pvt Ltd
Current assignee: Twenty First Century Pharmaceuticals Pvt Ltd
Priority date: 2020-05-16
Filing date: 2021-04-28
Publication date: 2021-11-25
Anticipated expiration: 2022-11-16

Abstract

Disclosed are pharmaceutical formulations comprising clavulanic acid granules prepared by granulating clavulanic acid with pH independent hydrophobic polymer and hydrophilic plasticizer in a non-aqueous solvent. Also, disclosed is pharmaceutical formulations of clavulanic acid granules and β-lactam antibiotic. The percentage of hydrophilic plasticizer and pH independent hydrophobic polymer used in the pharmaceutical formulation determines the rate of dissolution and stability for clavulanic acid.

Description

Field of the Invention

The present invention generally relates to the field of pharmaceutical preparations, and more particularly to method for improving dissolution and stability of clavulanic acid formulation using pH independent hydrophobic polymer and hydrophilic plasticizer. The invention also relates to pharmaceutical formulations of clavulanic acid with b-lactam antibiotic.

Background of the Invention

Amoxicillin and cephalosporins belongs to the group of broad spectrum b-lactam antibiotics whereas clavulanic acid is well-know b-lactamase inhibitor, and their combination is well-known for treating bacterial infections.

Amoxicillin is crystalline in nature, often lacking satisfactory flowability and density. Consequently, direct compressible grade materials are used to overcome flowability and density. Oral administration of cephalosporins tends to show bioavailability problems and slow dissolution.

Clavulanic acid stability is a key concern in developing pharmaceutical formulation. For preparing granules of potassium clavulanate, the situation is very complex due to its hygroscopic nature.

Clavulanic acid readily decomposes in presence of water during wet granulation.

With dry granulation process, amoxicillin trihydrate exhibit intimate contact with clavulanic acid, which results into degradation of clavulanic acid due to high water content in amoxicillin trihydrate.

Thus, there remains a need for alternate pharmaceutical formulation that prevents degradation of clavulanic acid due to moisture absorption both externally and from other active/inactive ingredients.

The inventors of the present invention have found that when a pH independent hydrophobic polymer is granulated with clavulanic acid in a non-aqueous solvent, the deterioration in the stability of clavulanic acid can be surprisingly prevented. Furthermore, a hydrophilic plasticizer is added to improve dissolution of clavulanic acid granules.

Summary of the Invention

In order to overcome the hygroscopic concern of clavulanic acid, and absorption of moisture from amoxicillin trihydrate and other pharmaceutically acceptable excipients in pharmaceutical formulations, there is provided a coating system and granulation technique to protect clavulanic acid from moisture absorption and thereby improving stability of clavulanic acid in the formulation.

The present invention provides granules prepared by granulating clavulanic acid with a pH independent hydrophobic polymer and a hydrophilic plasticizer in a non- aqueous solvent.

In one aspect of the present invention, the granulation is performed in a rapid mixer granulator using spray technique with help of peristaltic pump for controlled spray to avoid local wetting of clavulanic acid. The clavulanate granules preferably contains potassium clavulanate diluted with low moisture grade microcrystalline cellulose.

In another aspect of the present invention, the percentage of hydrophilic plasticizer and pH independent hydrophobic polymer used in a pharmaceutical formulation determines the rate of dissolution and stability for clavulanic acid.

In a further aspect of the present invention, the granulated clavulanic acid is blended with amoxicillin trihydrate to prepare pharmaceutical formulations.

In yet another aspect of the present invention, the granulated clavulanic acid is blended with a cephalosporin antibiotic to prepare pharmaceutical formulations. These and other aspects of the present invention will become apparent from the detailed description which follows and are accomplished by the invention as hereinafter described and claimed.

Brief description of drawings

The present invention may best be understood by reference to the following description, taken in connection with the accompanying drawings in which the reference numerals designate throughout the figures thereof and wherein:

Figure 1 : Open exposure study for potency evaluation of clavulanic acid in tablet

Figure 2: Dissolution profile of plain clavulanic acid and granulated clavulanic acid in tablet

Figure 3: Open exposure study for potency evaluation of clavulanic acid in dry powder suspension

Figure 4: Dissolution profile of plain clavulanic acid and granulated clavulanic acid in dry powder suspension

Detailed Description of the Invention

The following detailed description is presented to enable any person skilled in the art to make and use the invention. For purposes of explanation, specific nomenclature is set forth to provide a thorough understanding of the present invention. Flowever, it will be apparent to one skilled in the art that these specific details are not required to practice the invention. Descriptions of specific applications are provided only as representative examples. The present invention is not intended to be limited to the embodiments shown, but is to be accorded the broadest possible scope consistent with the principles and features disclosed herein.

The following definitions of general terms used herein apply irrespective of whether the terms in question appear alone or in combination. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an," and "the" include plural forms unless the context clearly dictates otherwise.

The words "comprise", "comprises", and "comprising" are to be interpreted inclusively rather than exclusively. The words "consist of", "consisting", and its variants, are to be interpreted exclusively, rather than inclusively.

The inventors of the present invention have found that when pH independent hydrophobic polymer and hydrophilic plasticizer is granulated with clavulanic acid in a non-aqueous solvent, the deterioration in the stability of clavulanic acid can be surprisingly prevented and also the dissolution is improved. As it is shown in the examples below, the percentage of hydrophilic plasticizer and pH independent hydrophobic polymer used, significantly prevents degradation and improves dissolution of clavulanic acid in a pharmaceutical formulation of the present invention.

The pharmaceutical formulation according to the present invention provides a granule containing clavulanic acid, pH independent hydrophobic polymer and hydrophilic plasticizer in a non-aqueous solvent.

In one embodiment, the present invention provides a granule containing clavulanic acid, a pH independent hydrophobic polymer, and a hydrophilic plasticizer in a non- aqueous solvent.

Suitable pH independent hydrophobic polymer includes ethyl cellulose and polyvinyl ethyl acetate. Ethyl cellulose is the preferred pH independent hydrophobic polymer.

Suitable hydrophilic plasticizer includes, but not limited to, polyethylene glycol, glycerin, propylene glycol, and sorbitol. Polyethylene glycol is the preferred hydrophilic plasticizer. The formulation of the present invention may optionally comprise at least one excipient, such as a filler, a sweetener, a disintegrant, a viscosity enhancer, a glidant, a flavor, and a pH modifier.

In another embodiment, the present invention provides a pharmaceutical formulation containing granules of clavulanic acid and amoxicillin trihydrate along with other pharmaceutically acceptable excipients.

In yet another embodiment, the present invention provides a pharmaceutical formulation containing granules of clavulanic acid and crystals of amoxicillin trihydrate.

The pharmaceutical formulations of the present invention can be prepared to provide immediate or modified release of the formulation.

As used herein the term “immediate release” refers to a formulation showing a release of active substance(s) which is not deliberately modified by a special formulation design and/or manufacturing method. In the case of a solid dosage form the dissolution profile of the active substance depends essentially on its intrinsic properties. This is further understood to be traditional or conventional release profile where no slow, delayed or extended-release effect is incorporated. Preferably, means that a percentage equal to or greater than 65% of the active ingredient is dissolved within 60 minutes, preferably within 30 minutes and more preferably within 15 minutes in a US Pharmacopeia type 1 apparatus in 0.05M acetate buffer, at pH 4.5, 100 rpm in a volume of 900 ml. More preferably the percentage of active ingredient dissolved is greater than 75%, more preferably greater than 80%.

The term “modified release” as used herein includes all types of modified release profiles such as controlled release, sustained release, delayed release, and the like.

The formulations of the present invention can be prepared by combining one or more dosage units in an oral formulation. These dosage units can be tablets, granules, pellets, capsules, or particles or combinations thereof. As it can be understood by the skilled person in the pharmaceutical industry, the term "granulation" refers to the act or process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Thus, it is the process of collecting particles together by creating bonds between them. Bonds are formed by compression or by using a binding agent. Granulation is extensively used in the manufacturing of tablets and pellets (or spheroids).

As used herein the term "tablet" includes tablets, mini tablets or micro tablets. Similarly, the term "capsule" also can refer to micro capsules. Suitable capsules may be either hard or soft, and are generally made of gelatin, starch, or a cellulosic material, gelatin capsules being preferred. Two-piece hard gelatin capsules are preferably sealed by gelatin bands or the like. In a preferred embodiment, said orally administrable pharmaceutical dosage form according to the invention is in the form of a capsule.

The pharmaceutical formulation of the present invention can be prepared as drug powder suspension or syrup for oral administration.

The term “b-lactam antibiotic” as used herein shall mean antibiotic and shall include amoxicillin and cephalosporin antibiotics.

The term "amoxicillin" as used herein shall mean amoxicillin, or any pharmaceutically acceptable salt thereof, in particular amoxycillin trihydrate and (crystallized) sodium amoxycillin, without distinction and unless otherwise indicated.

The term “clavulanic acid” as used herein shall mean clavulanic acid, or a pharmaceutically acceptable salt thereof. Examples of such salts include potassium, sodium, lithium, calcium and magnesium salts. Potassium clavulanate is the most preferred in the present invention. As used herein, the term “effective amount” means an amount necessary to achieve a selected result.

In another embodiment, the present invention provides a method for preparing pharmaceutical formulation by direct compression of granules of amoxicillin trihydrate and clavulanic acid. The method is carried out in an environment with a relative humidity of 20% or lower and at a temperature between 20 and 25°C because decomposition process in clavulanic acid starts with small amount of water as reaction product.

In another embodiment, the present invention provides a granulation method by granulating clavulanic acid with pH independent hydrophobic polymer and hydrophilic plasticizer having a weight gain 1 to 10%, preferably 1 to 6%. The granulated clavulanic acid is blended with granules of amoxicillin trihydrate, low moisture grade microcrystalline cellulose, disintegrant, glidant, and lubricant and is compressed into tablet with moisture barrier film coating.

In another embodiment, the present invention provides a wet granulation method by separately granulating amoxicillin trihydrate and clavulanic acid. The particles of clavulanic acid are partially covered with pH independent hydrophobic polymer in presence of hydrophilic plasticizer in a non-aqueous system in rapid mixer granulator. Amoxicillin crystals/granules are sieved, and other excipients are added to the mixture and clavulanic acid added extra granularly. The mixture thus prepared may be filled into sachets, glass or plastic bottles or the mixture is compressed into tablets.

In another embodiment, the present invention provides drug powder suspension comprising granules of clavulanic acid and crystals of amoxicillin trihydrate along with pharmaceutically acceptable excipients such as a sweetener, a viscosity enhancer, heavy and light colloidal silicon dioxide, a flavor, a filler, and a pH modifier. The drug powder suspension is processed in an environment with relative humidity of 15 to 20% at a temperature between 20 and 25°C. In another embodiment, the present invention provides dry powder syrup comprising cellulose diluted potassium clavulanate granulated with pH independent hydrophobic polymer in the presence of hydrophilic plasticizer.

In another embodiment, the present invention provides a pharmaceutical formulation containing granules of clavulanic acid and a cephalosporin antibiotic along with other pharmaceutically acceptable excipients.

The term “cephalosporin” as used herein shall mean cephalosporin antibiotic and may include, but not limited to, cefpodoxime proxetil, cefuroxime axetil, cefixime trihydrate, cefadroxil, cefatrizine, ceftibuten, cefalexin, cephradine and cefaclor.

In one embodiment, the cephalosporin used in the present invention is cefpodoxime proxetil. In another embodiment, the cephalosporin used in the present invention is cefuroxime axetil.

Manufacturing Process

The present invention provides a process for the preparation of a pharmaceutical formulation which comprises

(a) granulating clavulanic acid with pH independent hydrophobic polymer and hydrophilic plasticizer in non-aqueous solvent,

(b) blending granules of amoxicillin trihydrate with granules of clavulanic acid of step (a),

(c) blending extra granular excipients with step (b),

(d) compressing mixture of step (c) into tablets, and

(e) optionally film coating the tablets.

Manufacturing process is carried out at RH in the range of 15 to 20% and temperature in the range of 20 to 25°C. The following examples illustrate the pharmaceutical formulations of the invention. These formulations are not limitations on the present invention.

Example 1 Preparation of Amoxicillin and Potassium Clavulanate Tablet Formulation by dry granulation process

Table 1 : Tablets of the following composition were prepared

Crystals of Amoxicillin trihydrate, potassium clavulanate, sodium starch glycolate dried, microcrystalline cellulose dried and colloidal silicon dioxide were mixed in bin blender and sieved through mesh no. 20. Presifted magnesium stearate added into blender and mixed for 2 minutes. Dry mix blend was slugged using roll compactor or compression machine, the slugs were milled through 2mm screen using Comill. Presfited magnesium stearate added to milled granules and granules were compressed. The compressed tablet coated with film coat with the weight gain of 5% w/w. The final weight of film coated tablet is 1050mg. Example 2

Preparation of Amoxicillin and Potassium Clavulanate Tablet Formulation by wet granulation process

Table 2: Tablets of the following composition were prepared

Cellulose diluted potassium clavulanate granulated with binder ethyl cellulose and polyethylene glycol dried and milled through screen 1.5mm. Granules of Amoxicillin trihydrate, potassium clavulanate granules blended with microcrystalline cellulose, dried sodium starch glycolate, colloidal silicon dioxide and magnesium stearate. The granules compressed into tablet, film coating was performed over the core tablet. Film coated tablet manufactured in example 1 and example 2 are placed in separate petri dish tablets were exposed to temperature 20°C to 30°C with relative humidity 40% to 80%. The exposed tablets were analysed for potassium clavulanate assay at

8^th& 11^th day to determine the degradation of clavulanic acid. The assay values are enumerated in Table 3.

After exposure of tablets the potency of clavulanic acid as follows

Table 3: Open exposure study for potency evaluation of clavulanic acid

With ethyl cellulose granulation potassium clavulanate formulation found to be stable comparatively to plain clavulanic acid (non-granulated).

Dissolution of granulated clavulanic acid and plain clavulanic acid performed as per USP recommendation. The results are enumerated below,

Table 4: Dissolution for plain clavulanic acid vs coated clavulanic acid

The percentage clavulanic acid dissolved both in plain clavulanic acid and granulated clavulanic acid is similar in film coated tablet.

Example 3

Preparation of Amoxicillin and Potassium Clavulanate dry powder suspension

Table 5: Suspension of the following composition was prepared

During the preparation procedures the temperature was between 20 and 25°C and the relative humidity less than 20%. Dry powder suspension prepared by passing the ingredients through #60 mesh sieve blending together and filled in suitable container. Example 4

Preparation of Amoxicillin and Potassium Clavulanate dry powder suspension

Table 6: Suspension of the following composition was prepared

Cellulose diluted potassium clavulanic acid granulated with hydrophobic pH independent polymer in presence of hydrophilic plasticizer, the granules sifted through #40 mesh followed by sifting of amoxicillin trihydrate, filler, flavour, sweetener, pH modifier, viscosity modifier and colloidal silicon dioxide.

Dry powder suspension filled into HDPE container and exposed to temperature between 20 and 25°C and the relative humidity less than 20%. The container cap was open for 6 days and assay was performed to evaluate the degradation of clavulanic acid. Open exposure study of potassium clavulanate comprised oral dry suspension results are disclosed in below table

Table 7: Open Exposure Study for Dry Powder Suspension

Table 8: Dissolution of dry powder syrup for plain clavulanic acid vs coated clavulanic acid

Example 5

Preparation of Cefpodoxime Proxetil and Potassium Clavulanate Tablet Formulation by dry granulation process

Table 9: Tablets of the following composition were prepared

Cellulose diluted potassium clavulanate granulated with binder ethyl cellulose and polyethylene glycol dried and milled through screen 1.5mm. Cefpodoxime proxetil, potassium clavulanate granules blended with croscarmellose sodium, microcrystalline cellulose, sodium lauryl sulphate and aerosol. The granules compressed into tablet, film coating was performed on tablet. Example 6

Preparation of Cefpodoxime Proxetil and Potassium Clavulanate Dry Powder Suspension

Table 10: Suspension of the following composition was prepared

Cellulose diluted potassium clavulanic acid granulafed with hydrophobic pH independent polymer in presence of hydrophilic plasticizer, the granules sifted through #40 mesh followed by sifting of cefpodoxime proxetil, filler, flavour, sweetener, pH modifier, viscosity modifier and colloidal silicon dioxide.

Example 7 Preparation of Cefpodoxime Proxetil and Potassium Clavulanate Dispersible Tablet

Table 11 : Dispersible Tablet of the following composition was prepared Cellulose diluted potassium clavulanate granulated with binder ethyl cellulose and polyethylene glycol dried and milled through screen 1.5mm. Cefpodoxime proxetil granulated with ethyl cellulose as taste masking polymer. Granules of Cefpodoxime Proxetil, potassium clavulanate, croscarmellose sodium dried, microcrystalline cellulose dried, sucralose, orange flavor, colorant and aerosil were sifted through # 40 mixed in bin blender. Presfited magnesium stearate added to milled granules and granules were compressed into tablet.

Example 8 Preparation of Cefuroxime Axetil and Potassium Clavulanate Tablet Formulation

Table 12. Tablets of the following composition was prepared

Cellulose diluted potassium clavulanate granulated with binder ethyl cellulose and polyethylene glycol dried and milled through screen 1.5mm. Cefuroxime Axetil, potassium clavulanate granules, Croscarmellose sodium, microcrystalline cellulose, crospovidone, sodium lauryl sulphate, and aerosil were sifted through # 40 mixed in bin blender. Presfited magnesium stearate added to milled granules and granules were compressed into tablet followed by aqueous film coat with Opadry Amb II.

Example 9

Preparation of Cefixime Trihydrate and Potassium Clavulanate Tablet Formulation

Table 13. Tablet of the following composition was prepared

Cellulose diluted potassium clavulanate granulated with binder ethyl cellulose and polyethylene glycol dried and milled through screen 1.5mm. Cefixime trihydrate, potassium clavulanate granules, Croscarmellose sodium, microcrystalline cellulose, and aerosil were sifted through # 40 mixed in bin blender. Presfited magnesium stearate added to milled granules and granules were compressed into tablet followed by aqueous film coat with Opadry Amb II.

Example 10

Optimization of PEG contraction

Different concentration of hydrophilic plasticizer used in the granulation process to evaluate clavulanic acid rate of release during dissolution and degradation of clavulanic acid in hold study at ambient condition.

Table 14: Tablets of the following composition were prepared

Table 15: Dissolution for granulated clavulanic acid

The percentage of hydrophilic plasticizer to pH independent hydrophobic polymer was selected from 10% to 20% and a trail without hydrophilic plasticizer. In absence of plasticizer dissolution was slow and with 20% of plasticizer dissolution was found fast. On hold study in ambient condition with 20% of hydrophilic plasticizer significant colour change observed with granulated clavulanic acid. Interestingly with 10% of hydrophilic plasticizer, no colour change was observed. With 10% of hydrophilic plasticizer, process found to be satisfactory, and release of clavulanic acid found to be satisfactory. With 10% of PEG, the degradation of clavulanic acid was found to be least.

Example 11 Optimization of pH independent hydrophobic polymer (ethylcellulose) in granulation of clavulanic acid

Different concentration of pH independent hydrophobic polymer (ethylcelulose) was used in the granulation process to evaluate stability of clavulanic acid

Table 16: Tablets of the following composition were prepared

In #1 , ethyl cellulose 3% was used for granulating clavulanic acid and during coating process, colour change was observed. In #3 and #4, ethyl cellulose 10% & 13% was used for granulating clavulanic acid and it was observed that while compression, disintegrating and dissolution were out of specification.

With ethyl cellulose 7% as granulating polymer no colour change was observed, and disintegration and dissolution were within the limit. Hence, with 7% ethyl cellulose, clavulanic acid was found to be stable.

The above description is for the purpose of teaching the person of ordinary skill in the art how to practice the present invention, and it is not intended to detail all those obvious modifications and variations of it which will become apparent to the skilled worker upon reading the description. It is intended, however, that all such obvious modifications and variations be included within the scope of the present invention, which is defined by the following claims. The claims are intended to cover the claimed components and steps in any sequence which is effective to meet the objectives there intended, unless the context specifically indicates the contrary.

Claims

Claims We claim -

1. A pharmaceutical formulation comprising

(a) granules comprising

(i) an effective amount of clavulanic acid or a pharmaceutically acceptable salt thereof,

(ii) a pH independent hydrophobic polymer,

(iii) a hydrophilic plasticizer, and

(iv) a non-aqueous solvent,

(b) an effective amount of b-lactam antibiotic, and

(c) a pharmaceutically acceptable excipient.

2. The pharmaceutical formulation as claimed in claim 1 , wherein the pH independent hydrophobic polymer is selected from the group consisting of ethyl cellulose and polyvinyl ethyl acetate.

3. The pharmaceutical formulation as claimed in claim 1 , wherein the hydrophilic plasticizer is selected from the group comprising of polyethylene glycol, glycerin, propylene glycol and sorbitol.

4. The pharmaceutical formulation as claimed in claim 1 , wherein the non- aqueous solvent is low moisture grade microcrystalline cellulose.

5. The pharmaceutical formulation as claimed in claim 1 , wherein the formulation is an immediate release formulation.

6. The pharmaceutical formulation as claimed in claim 2, wherein the formulation is a modified release formulation.

7. The pharmaceutical formulation as claimed in claim 1 , wherein clavulanic acid salt is potassium clavulanate.

8. The pharmaceutical formulation as claimed in claim 1 , wherein the b-lactam antibiotic is selected from the group consisting of amoxicillin trihydrate, cefpodoxime proxetil, cefuroxime axetil and cefixime trihydrate.

9. The pharmaceutical formulation as claimed in claim 1 , wherein the formulation is an oral formulation.

10. The pharmaceutical formulation as claimed in claim 2, wherein the formulation is in a form selected from the group comprising of a tablet, pellet, capsule, solution, syrup, suspension, granule, and powder.

11. A process for the preparation of a pharmaceutical formulation, which comprises step of:

(a) granulating clavulanic acid or a pharmaceutically acceptable salt thereof with a pH independent hydrophobic polymer and a hydrophilic plasticizer in a non-aqueous solvent,

(b) blending a b-lactam antibiotic with granules of step (a), and

(c) compressing the blend of step (b) to form a tablet.

12. The process as claimed in claim 11 , wherein further comprises step of film coating the tablet.

13. The process as claimed in claim 11 , wherein the process comprises optional step of blending step (b) with extra granulator excipients.

14. The process as claimed in claim 11 , wherein the process is carried out at relative humidity of from 15 to 20% at a temperature of from 20 to 25°C.

15. The process as claimed in claim 11 , wherein the b-lactam antibiotic is in a form of crystals.

16. The process as claimed in claim 11 , wherein the b-lactam antibiotic in a form of granules.