WO2016046693A1

WO2016046693A1 - A co-processed pharmaceutical excipient

Info

Publication number: WO2016046693A1
Application number: PCT/IB2015/057095
Authority: WO
Inventors: Sandeep Vinodkumar NATHWANI; Jaydip Mansukhbhai VASOYA; Rachana Sandeep NATHWANI
Original assignee: Individual
Current assignee: Individual
Priority date: 2014-09-25
Filing date: 2015-09-15
Publication date: 2016-03-31
Anticipated expiration: 2017-03-25

Abstract

The Present invention provides a co-processed pharmaceutical excipient comprising synergistic combination of polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose (MCC) and also provides its preparation and its use in composition. A co-processed pharmaceutical excipient as per the present invention having excellent flowability and compressibility.

Description

A CO-PROCESSED PHARMACEUTICAL EXCIPIENT

FIELD OF INVENTION

The present invention pertains to a co-processed excipient, its preparation and its use in composition, wherein said co-processed pharmaceutical excipient comprising polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose (MCC).

BACKGROUND OF INVENTION

Discrete dosages of pharmaceutical compositions suitable for oral administration are conveniently administered as solid dosage forms, typically tablets. In addition to the therapeutic ingredient or ingredients (commonly referred to as "actives," "active pharmaceutical ingredients," or "API"), the tablet comprises pharmaceutically acceptable materials, known as excipients, that are not actives and do not provide a therapeutic effect, but are added to the tablet formulation to confer specific properties not related to the activity of the active.

There are three general methods of preparing the materials to be included in the solid dosage form prior to compression: (1) dry granulation; (2) direct compression; and (3) wet granulation. Dry granulation procedures may be utilized when one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tableted. The method includes mixing the ingredients, slugging the ingredients, dry screening, lubricating and finally compressing the ingredients. In direct compression, the powdered material(s) to be included in the solid dosage form is compressed directly without modifying the physical nature of the material itself. The wet granulation procedure includes mixing the powders to be incorporated into the dosage form in, e.g., a twin shell blender or double-cone blender and thereafter adding solutions of a binding agent to the mixed powders to obtain a granulation. Thereafter, the damp mass is screened, e.g., in a 6- or 8-mesh screen and then dried, e.g., via tray drying, the use of a fluid-bed dryer, spray-dryer, radio-frequency dryer, microwave, vacuum, or infra-red dryer.

A limitation in the use of the direct compression method is that the drug or active ingredient must have the requisite crystalline structure and physical characteristics required for formation of a pharmaceutically acceptable tablet. It is well known in the art, however, that one or more excipients can be included to make the direct compression method applicable to drugs or active ingredients which do not possess the requisite physical properties. For solid dosage forms wherein the drug itself is to be administered in a relatively high dose (e.g., the drug itself comprises a substantial portion of the total tablet weight), it is necessary that the drug(s) itself have sufficient physical characteristics (e.g., cohesiveness) for the ingredients to be directly compressed.

Typically, when making direct compression formulations, excipients which impart good flow and compression characteristics to the material as a whole are added to the formulation which is to be compressed. These desirable properties are commonly imparted to these excipients via a pre-processing step such as wet granulation, slugging, spray drying, spheronization, or crystallization. Useful direct compression excipients include processed forms of cellulose, sugars, and dicalcium phosphate dihydrate, among others. A processed cellulose, microcrystalline cellulose, has been utilized extensively in the pharmaceutical industry as a direct compression vehicle for solid dosage forms.

Another limitation in the use of direct compression as a method of tablet manufacture is the size of the tablet. If the amount of active ingredient is high, a pharmaceutical formulator may choose to wet granulate the active ingredient with other excipients to attain an acceptably sized tablet with the desired compact strength. This is because the amount of filler/binder or excipients usually needed in wet granulation is less than that required for direct compression because the process of wet granulation contributes to some extent toward the desired physical properties of a tablet. Thus, despite the advantages of direct compression (such as reduced processing times and costs), wet granulation is widely used in the industry in the preparation of solid dosage forms. Many of those skilled in the art prefer wet granulation as compared to direct compression because this method has a greater probability of overcoming any problems associated with the physical characteristics of the various ingredients in the formulation, thereby providing a material which has the requisite flow and cohesive characteristics necessary to obtain an acceptable solid dosage form.

Due to the popularity of microcrystalline cellulose, pharmaceutical formulators have deemed it desirable to include this excipient in a formulation which is wet granulated prior to tableting. Unfortunately, currently-available microcrystalline cellulose does not hold to the typical principle that the amount of filler/binder needed in wet granulation is less than that in direct compression. It is known that the exposure of the microcrystalline cellulose to moisture in the wet granulation process severely reduces the compressibility of this excipient. The loss of compressibility of microcrystalline cellulose is particularly problematic when the formulation dictates that the final product will be relatively large in the environment of use. For example, if a pharmaceutical formulator desires to prepare a solid oral dosage form of a high dose drug, and the use of the wet granulation technique is deemed necessary, the loss of compressibility of the microcrystalline cellulose dictates that a larger amount of this material may be needed to obtain an acceptably compressed final product. The additional amount of microcrystalline cellulose needed adds cost to the preparation, but more importantly adds bulk, making the product more difficult to swallow. The loss of compressibility of microcrystalline cellulose when exposed to wet granulation has long been considered a problem in the art for which there has been no satisfactory solution. This problem has recently been overcome with the introduction of PROSOLV SMCC™, commercially available from Penwest Pharmaceuticals Co., and described and covered by U.S. Pat. Nos. 5,866,166; 5,725,884; 5,725,883; and 5,585,115, among others. PROSOLV SMCC™ is a silicified microcrystalline cellulose. Silicification of the microcrystalline cellulose is achieved by a patented process, resulting in an intimate association between the colloidal silica and microcrystalline cellulose. This product is available in a median particle size (by sieve analysis) in the region of 50 μιη and 90 μιη.

Disintegrants are often included in order to ensure that the ultimately prepared compressed solid dosage form has an acceptable disintegration rate in an environment of use (such as the gastrointestinal tract). Typical disintegrants include starch derivatives (including gelatinised starches (e.g., Sta Rx™) or modified starches, e.g. sodium starch glycolate ("SSG")(e.g., Primojel™)), and salts of carboxymethyl cellulose. Some of these disintegrants are called superdisintegrants because of their high efficiency, even at low concentration, and because of their high swelling capacity in the presence of water. It is also known that some materials, such as microcrystalline cellulose (e.g., Avicel PH101.R™ and Avicel PH102.R™, described in U.S. Pat. Nos. 2,978,446; 3,141,875 and 3,023,104) present binding and disintegrating characteristics and therefore are useful both as a binder and a disintegrant. Swelling is one of the decisive factors influencing the disintegrant behavior of compacted pharmaceutical dosage forms and consequently the biopharmaceutical profile of drug substances. Among the various excipients used to promote the disintegration of such dosage forms in its originally primary particles, several substances, classified as swelling disintegrants, are employed.

One commercially available superdisintegrant, Ac-Di-Sol® (which is the acronym of Accelerated Dissolution), (Croscarmellose Sodium) (FMC Corporation) is an internally cross- linked form of sodium carboxymethylcellulose (NaCMC or "SCMC"). Ac-Di-Sol differs from soluble sodium carboxymethylcellulose only in that it has been cross-linked to ensure that the product is essentially water insoluble. It is an odorless, relatively free flowing, white powder. Internal cross-linking is induced by lowering the pH of NaCMC in solution and then heating it, with no chemical additives used. Initially soluble, the cross-linked NaCMC is virtually insoluble, yet still very hydrophillic and therefore swellable. Ac-Di-Sol is said to be effective in both direct compression and wet granulation formulations. The amount of Ac-Di-Sol used in direct compression tableting may vary with typical usage levels between 1 and 3 percent, and the amount of Ac-Di-Sol used in capsule formulations generally ranges from 4-6 percent. Ac- Di-Sol is said to be covered by U.S. Pat. No. 5,272,191. This product is said to be obtained by internally cross-linking sodium carboxymethylcellulose. The cross-linking is said to be achieved thermally without the use of any chemical additive (viz. cross -linking agent) to create a bridge between the macromolecular chains of cellulose. Ac-Di-Sol is said to quickly absorb high amounts of water by swelling, thereby leading to the disintegration of the tablet.

Cross-linked amylose tablets have a low degree of cross-linking swell in aqueous media. International Patent Application No. WO 94/21236 describes powders of cross-linked amylose having a specific cross-linking degree for use as a binder/disintegrant in tablets prepared by direct compression. (See also U.S. Pat. No. 5,456,921 and International Patent Application No. WO 94/02121). Powders of cross-linked amylose with a high cross-linking degree are said to allow tablets to disintegrate quickly by their high capacity of water absorption and their swelling power.

More recently, U.S. Pat. No. 5,989,589 described cross-linked cellulose as a binder disintegrant that can be used in the preparation of pharmaceutical tablets. The binder disintegrant is more specifically said to be a non-swelling cross-linked cellulose having a cross-linking degree ranging from 2 to 50, and is said to be prepared by cross-linking a cellulose (fibrous cellulose or microcrystalline cellulose) with a cross-linking agent (epichlorhydrin, sodium trimetaphosphate, adipic-acetic anhydride, phosphorous oxychloride, formaldehyde and diexpoxides) in a relative amount of 2-50 g of cross-linking agent per 100 g of cellulose.

Another commercially available superdisintegrant, Explotab® and Explotab® CLV (Penwest Pharmaceuticals Co.) is a cross-linked, low-substituted carboxymethyl ether of poly- a-glucopyranose obtained by the suitable treatment of potato starch and has a medium particle size in the range of 35-55 μιη. About 50-60 of the glucose units are carboxymethylated. Explotab® CLV differs from standard Explotab® by being more highly cross-linked, resulting in lower viscosity. Explotab® CLV has been demonstrated to be remarkably effective for rapid disintegration and enhanced dissolution when incorporated in tablet formulations prepared by direct compression or wet or dry granulation techniques. The mechanism by which this action takes place involves accelerated absorption of water, leading to an enormous increase in the volume of granules. This results in rapid and uniform tablet disintegration. Explotab® CLV is designed for use in wet granulation processes which utilize modem high-shear, high-speed granulating equipment. It is designed to give the same rapid disintegration as Explotab®, but incorporates qualities which make it more resistant to the rigors of the high- shear granulation process. Explotab® CLV provides desired results at use levels, e.g., between 2-4%. However, it is recommended that the proportion to be included in each individual formulation be determined experimentally.

Each of the above-mentioned U.S. Patents and International Patent Publications are hereby incorporated by reference.

Despite the existence of many binders and disintegrants, there still remains a need in the industry for pharmaceutical excipient which is highly compactible and multifunctional and improve the flow properties and compressibility of poorly compressible active ingredient.

An inventor has surprisingly found solution for above said unmeet need by preparing co-processed excipient comprising synergistic combination of polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose.

OBJECT OF INVENTION

An object of the present invention is to provide a co-processed pharmaceutical excipient having excellent flowability and compressibility.

Another object of the present invention is to provide directly compressible co-processed pharmaceutical excipient.

Another object of the present invention is to provide said co-processed pharmaceutical excipient comprising polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose.

Another object of the present invention is to provide process for preparation of said co- processed excipient.

Another objet of the present invention is to provide pharmaceutical composition comprising active ingredient, co-processed pharmaceutical excipient polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose and one or more pharmaceutically acceptable excipient.

DETAILED DESCRIPTION OF INVENTON

The co-processed pharmaceutical excipient of the present invention provides greatly enhanced characteristics like flowability, compressibility and other physiochemical properties.

The co-processed pharmaceutical excipient of the present invention is having excellent properties as directly compressible excipient for use in preparation of solid oral dosage form. As per the preferred embodiment a co-processed pharmaceutical excipient according to present invention comprising co-processed mixture of polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose.

As per the preferred embodiment a co-processed pharmaceutical excipient according to present invention comprising co-processed mixture of polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose and one or more pharmaceutically acceptable excipient. As per another embodiment a co-processed pharmaceutical excipient according to present invention is consisting essentially of polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose.

As per another embodiment a co-processed pharmaceutical excipient according to present invention is consisting essentially of co-processed polacrilin potassium, partially pregelatinized starch, microcrystalline cellulose and one or more pharmaceutically acceptable excipient.

The inventors have found that instead of using excipients separately or individually to produce certain effect, it is more advantageous to combine and formulate the excipients in such a way that they produce a synergistic effect. The present invention relates to the synergistic effect produced by the excipient composition which comprises a co-processed pharmaceutical excipient comprises of polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose.

The term "co-processed excipient" as used herein, refers to a mixture comprising polacrilin potassium, partially pregelatinized starch, microcrystalline cellulose, that have been co-processed using various means such as co-milling, mechanical milling, spray drying, freeze- drying, etc. As per preferred embodiment a co-processed pharmaceutical excipient comprising polacrilin potassium, partially pregelatinized starch and MCC, wherein ratio of; a) , polacrilin potassium to partially pregelatinized starch is in range of 1: 1.5 to 1: 2 b) . polacrilin potassium to MCC is in range of 1:2 to 1:3.5

As per another embodiment a co-processed pharmaceutical excipient comprising polacrilin potassium is present in amount range from 12 to 22% w/w, partially pregelatinized starch is present in amount range from 25 to 35% w/w and MCC is present in amount range from 40 to 58 % w/w of total weight of co-processed excipient.

As per another embodiment a directly compressible co-processed pharmaceutical excipient comprising polacrilin potassium, partially pregelatinized starch, microcrystalline cellulose and one or more pharmaceutically acceptable excipient selected from lubricant and sweetener.

For the purpose of present invention lubricant is Aerosil® and sweetener is Neotame, Alitame, Saccharine, Saccharine sodium. As per preferred embodiment, the co-processed pharmaceutical excipient according to present invention is prepared by spray drying method.

As per preferred embodiment, the process for preparation of co-processed pharmaceutical excipient according to present invention comprising the step of a) dispersion of MCC, partially pregelatinised starch, polacrillin potassium and a glident and a sweetener in water under stirring; b) spray drying the dispersion of step a) and c) spray dried product of step b) is packed in container.

As per another embodiment the present invention provides use co-processed pharmaceutical excipient comprising polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose for different kind of solid dosage form in pharmaceutical industry.

A co-processed pharmaceutical excipient as per the present invention has shows excellent flowability and compressibility and inventors have found that the co-processed pharmaceutical excipient with such excellent characteristics has advantage to use for preparation of directly compressible dosage form or to improve the flow properties or compressibility of poorly compressible excipient or such co-processed pharmaceutical excipient can be used during preparation of pharmaceutical dosage form wherein flow properties of excipient play critical role of manufacturing like granulation, mixing, compression or filling.

Inventors of the present invention have developed and prepared a multifunctional co- processed excipients comprising synergistic combination of polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose having characteristic of excellent flowability and compressibility and said co-processed pharmaceutical excipient has multiple gainful application for preparation of pharmaceutical dosage form. A single multifunctional co- processed pharmaceutical excipient as per the present invention reduces the requirement of multiple excipient for different function, reduce the processing step and makes manufacturing process simple, economical and efficient. The synergistic co-processed combination of polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose results in single excipient which improve the flowability and compressibility of an active ingredient that has poor pharmaceutical characteristics like poor flow, low bulk density and low compressibility without compromising the disintegration rate or dissolution rate or friability of pharmaceutical dosage form. The excellent flowability and compressibility of a co-processed pharmaceutical excipient of the present invention makes it unique single excipient for wide range of applicability for preparation of pharmaceutical dosage form, specifically solid dosage form. The uniqueness of co-processed pharmaceutical excipient of the present invention make it most preferable and efficient excipient for preparation of directly compressible tablet, to improve the flow of an active ingredient or pharmaceutical mixture for uniform mixing and granulation and to make efficient and uniform filing capsules.

A co-processed pharmaceutical excipient as present invention is useful for preparation of directly compressible immediate release or dispersible or disintegration or dissolving or chewable tablet, granulation of an active agent having poor flowability or having low bulk density, uniform mixing of pharmaceutical mixture and improve the flow for capsule filing.

As per another embodiment the present invention provides pharmaceutical composition comprising a) an active ingredient; b) a co-processed pharmaceutical excipient comprising polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose; and c) one or more pharmaceutically acceptable excipient. As per another embodiment the present invention provides pharmaceutical composition comprising a) an active ingredient; b) a co-processed pharmaceutical excipient comprising polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose wherein ratio of i) . polacrilin potassium to partially pregelatinized starch is in range of 1: 1.5 to 1: 2; ii) . polacrilin potassium to MCC is in range of 1:2 to 1:3.5 and c) one or more pharmaceutically acceptable excipient.

As per another embodiment the present invention provides pharmaceutical composition comprising a) an active ingredient; b) a co-processed pharmaceutical excipient comprising polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose and one or more pharmaceutically acceptable excipient selected from lubricant and sweetener and c) one or more pharmaceutically acceptable excipient.

As per another embodiment the present invention provides pharmaceutical composition comprising a) an active ingredient; b) a co-processed pharmaceutical excipient comprising polacrilin potassium in amount range from 12 to 22% w/w, partially pregelatinized starch in amount range from 25 to 35% w/w and MCC in amount range from 40 to 58 % w/w of total weight of co- processed pharmaceutical excipient and c) one or more pharmaceutically acceptable excipient.

For the purpose of the present invention, an active ingredient is selected from class of drug having poor flowability and/or compressibility or an active ingredient required improvement of flowability and/or compressibility for preparation of finished solid dosage form.

For the purpose of the present invention, an active ingredient is selected from following therapeutic classes but not limited to analgesics, anti-inflammatory agents, antihelminthics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, antidepressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, antihypertensive agents, anti-malarial, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.

Specific, non-limiting examples of suitable active ingredients for purpose of the present are selected from Ibuprofen, Acetamenophen (Paracetamol), Cimetidine, Metformine, Cefixime trihydrate, Cefuroxime axetil, Metronidazole and Azithromycin.

For the purpose of the present invention Ibuprofen is selected as model drug because Ibuprofen is best example of active pharmaceutical ingredient having high-dose poorly compressibility. Its challenging to improve compressibility and flow property of such type of active pharmaceutical ingredient as limited quantity of excipient can be incorporated in the unite formula. However, the scope of the present invention is not limited to any specific individual active pharmaceutical ingredient.

The invention is illustrated by the following example which is only meant to illustrate the invention and not act as limitations. All embodiments apparent to a process their in the art are deemed to fall within the scope of the present invention.

Example 1: Co-processed Excipient Composition

Neotame - 0.5 0.5 0.5 0.5

Manufacturing Process: a) dispersion of MCC, partially pregelatinised starch, polacrillin potassium and a glident and a sweetener in water under stirring to form 10% w/v disprsion; b) spray drying the dispersion of step a) at inlet air temperature 200 C, outlet air temperature 100 C, feed rate 4 ml/min, aspiration rate 55 Nm³/hr. and atomization pressure 1.5 bar and c) spray dried product of step b) is packed in container.

Various indexes an accordingly powder flow characteristics for Example 1

Example 2: Co-processed excipient composition

A co-processed excipient is prepared according process of example 1. Various indexes an accordingly powder flow characteristics for Examples 2

Example 3: Comparison between co-processed excipient and simple physical mixture.

A co-processed excipient as per Example 2(2). Same amount of these excipients are mixed simply to form physical mixture.

Pre-compression evaluation parameters data reflects that a co-processed pharmaceutical excipient prepared as per the example 1 and 2 shows significant improvement compare to simple physical mixture in pre-compression parameter. The data of Angle of repose and Hsuner's ration proves that a co-processed pharmaceutical excipient as per the present invention having good flow properties and the values of Carr's index parameter indicates towards good compressibility characteristic.

Example 6: Tablet composition

Manufacturing Process:

a) Mix a co-processed excipient as per the present invention with model drug;

b) mix magnesium stearate with mixture of step a) and

c) compression of final blend of step b) to form tablet.

Example 7: Various indexes for tablet properties of Example 6.

Claims

A co-processed pharmaceutical excipient comprising co-processed mixture of polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose.

The co-processed pharmaceutical excipient as claimed in claim 1 wherein ratio of a) , polacrilin potassium to partially pregelatinized starch is in range of 1: 1.5 to 1: 2 b) . polacrilin potassium to MCC is in range of 1:2 to 1 :3.5

The co-processed pharmaceutical excipient as claimed in claim 1 wherein polacrilin potassium is present in amount range from 12 to 22% w/w, partially pregelatinized starch is present in amount range from 25 to 35% w/w and MCC is present in amount range from 40 to 58 % w/w of total weight of co-processed excipient.

The co-processed pharmaceutical excipient as claimed in claim 1 further comprises one or more pharmaceutically acceptable excipient.

The co-processed pharmaceutical excipient as claimed in claim 4 wherein one or more pharmaceutically acceptable excipient is selected from lubricant and sweetener.

A co-processed pharmaceutical excipient consisting essentially of polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose.

The pharmaceutical composition comprising

a) , an active ingredient;

b) . a co-processed pharmaceutical excipient comprising polacrilin potassium, partially pregelatinized starch and microcrystalline cellulose; and

c) . one or more pharmaceutically acceptable excipient.