WO2009153798A1

WO2009153798A1 - Cross-linked dextrin as a tablet disintegrant/excipient

Info

Publication number: WO2009153798A1
Application number: PCT/IN2008/000376
Authority: WO
Inventors: Satyanarayana Kota; Rambhau Devraj; Bhujanga Rao Adibhatla Kali Satya; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Ltd
Current assignee: Natco Pharma Ltd
Priority date: 2008-06-16
Filing date: 2008-06-16
Publication date: 2009-12-23
Anticipated expiration: 2010-12-16

Abstract

Disintegrants are the essential components of a tablet. Cross-linking of dextrin with epichlorohydrin induces hydrophobization in hydrophilic dextrin. This in turn gives good swelling power in water. Dextrin is cross-linked with various ratios of epichlorohydrin to dextrin by weight. Cross-linking is done from 5-50% ratio of epichlorohydrin. The swelling capacity is highest with 20% cross-linking. The cross-linked dextrin is evaluated for disintegrating action by preparation of paracetamol tablets by wet granulation method and folic acid tablets by direct compression technique. In wet granulation technique, tablets prepared using 20% cross-linked dextrin disintegrated in less than one minute and by direct compression technique tablet disintegrated in less than four minutes.

Description

Cross-linked Dextrin as a Tablet Disintegrant/Excipient

Field of the Invention The present inventions deals with use of cross-linked dextrin as disintegrant in a pharmaceutical tablet formulation.

Background

Tablet dosage form is most widely used, popular, convenient solid dosage form. A tablet contains drugs and excipients. Excipients are non-active ingredients, which are mixed with pharmacologically active compounds (drug/active pharmaceutical ingredient). Excipients used in tablet formulation are binders, disintegrants, diluents, lubricants, glidants, surfactants, dyes and flavouring agents.

Disintegrants are the important component of the tablet excipients. Disintegrants are usually added to cause the compressed tablet to break apart when placed in aqueous medium. Typical disintegrants are maize, potato starch, gelatinized starches, alginic acid crosscarmellose, crdsspovidone, sodium starch glycolate etc. Disintegrants swell on contact with water, which cause the tablet to break.

The classical disintegrants such as starches of maize, corn, tapioca, wheat, potato, and alginic acid etc. are used in 5-20% w/w of tablet. Tablets made using these disintegrants typically exhibit disintegration time about 10-30 min at hardness of 6-8 kg.

Superdisintegrants are new class of disintegrants, which are used in 1-10% w/w of the tablet weight. Superdinsintegrants exhibit disintegration time of 1- 5 minutes. In some cases even less than 1 min. At present there are 3-4 superdinsintegrants, which are used industrially. These are crosscormellose sodium (Sodium salt of cross-linked, partly O- carboxymethylated cellulose, Ac-Di-SoI), Sodium starch glycolate (O-carboxymethy starch, primojel or Explotab), Crosspovidone (Polyplasdorie XL) etc. (http://pharmtech.findpharmaxom/ρharmtech/Excipients/A-Comρarative-Study-of- Current-Superdisintegrants/ArticleStandard/Article/detail/378399)

Number of superdinsintegrants available in the market are less and available ones are expensive, hence there great need for safe, effective and reasonable priced superdisintegrant

Dextrin is a starch derivative, is chemically a mixture of polymerized glucosans with molecular formula of (CgHiOOs)_nXH₂O. It is low molecular weight carbohydrate obtained by partial hydrolysis of starch of by heat, alkali, and enzymes. Starch source may be from maize, corn, potato etc. Dextrin is available in two grades based upon the solubility. White dextrin is partially soluble in water, whereas yellow dextrin is completely soluble in water. Dextrin is commercially available in abundant quantities quite economically.

US patent 3,275,576 (1966) describes the preparation of dextrin cross-linked with epichlorohydrin, bis-epoxypropylether, ethylene glycol-bis-epoxy propyl ether and its potential application as cation-exhanger.

US patent 4,010, 259 (1977) describes the preparation of dextrin cross-linked with epichlorohydrin and its inclusion complex with iodine for potential use as iodophore. Cross-linked dextrin is also suggested for applications such as wastewater treatment etc. However to our knowledge, there is no description of cross-lined dextrin as tablet excipients and particularly as tablet disintegrant in the literature. This patent describes the improved process preparation of cross-linked dextrin and its use as tablet disintegrant, diluent and binder. Summary of the Invention

Dextrin is partially hydrolyzed starch. It is partially or completely soluble in water depending on the degree of hydrolysis. White dextrin is partially soluble in water, whereas yellow dextrin is completely soluble in water. Treating the hydroxy groups of polysaccharide dextrin with bifunctional cross-linking agentyield cross-linked dextrin. Cross-linking induces hydrophobization to hydrophilic dextrin, which in turn induces swelling property to dextrin in water. The objective of the present invention is to describe tablet-disintegrating property of cross-linked dextrins.

The main objective of present invention is to cross-link dextrin with 2-50 g cross-linking agent per 100 g dextrin to produce 2-50% cross-linked dextrin. The important objective of present invention is to use cross-linked dextrin as disintegrant in the formulation of tablets prepared by wet granulation in ratio of 0.1-20 g per 100 gram tablet granules, which show the disintegration time of less than 1 minute to 20 minutes.

Yet another objective of present invention is to use cross-linked dextrins as disintegrant in the formulation of tablets prepared by direct compression method in ratio of 0.1-20 g per 100 gram tablet granules which show the disintegration time of less than 1 minute to

20minutes.

Detailed Description of the Invention

The two carbohydrate chains present in the dextrin can be linked by a bifunctional linking agent by a covalent bond. In this linkage reaction, the hydroxy groups of the chains are involved. A typically cross-linked dextrin can be depicted as follow.

The degree of cross linking is from 2 to 50, preferably from 20 to 50, and it is prepared by cross-linking dextrin with a cross-linking agent in a relative amount of 2 to 50 g of cross-linking agent per 100 g of dextrin is employed. Cross-linked dextrin having degree of cross-linking less than 15% is found to be soluble in water and between 15-20% is partially soluble in water. Cross-linked dextrins with degree of cross-linking greater than 20% are found to be insoluble in water.

The cross-linking agent used to cross-link dextrin can be epichlorohydrin, bis- epoxypropylether, ethylene glycol-bis-epoxy propyl ether, sodium trimetaphosphate (STMP), adipic-acetic anhydride, phosphorus oxy chloride, formaldehyde or a diepoxide, such as vinylcyclohexene dioxide or butadiene dioxide, vinylcyclohexene dioxide or butadiene dioxide. Preferably, use is made of epichlorohydrin.

Disintegrating property of a disintegrant is related to swelling capacity of the material in water. Dextrin cross-linked with 20, 25, 30, 35, 40, 45, 50% epichlorohydrin are evaluated for swelling property in water for different time intervals. For evaluation of swelling capacity, 1 gram of dextrin cross-linked with various percentages of cross- linking agent is taken in 50 ml graduated, stoppered measuring cylinder and water is added till 40 ml mark and shaken gentle for 30 seconds and further water is added till 50 ml mark and allowed stand for 240 minutes. The swelling capacity is noted at 15, 30, 60, and 240 minutes. The highest swelling capacity of 12 ml is observed with 20% cross- linked, which is selected for further evaluation of disintegrating property. Dextrin cross- linked with less than 20% cross-linking are found to be either completely or partially soluble in water. Swelling capacity of dextrin cross-linked with epichlorohydrin with 20- 50% cross-linking agent is shown in Tablel.

Evaluation of Disintegrant Property

For evaluation of disintegrating property, tablets are initially prepared using 20% cross- linked dextrin (CLD-20) by wet granulation method. These tablets are prepared using paracetamol as active pharmaceutical ingredient, dicalcium phosphate as diluent, starch paste as binder and magnesium stearate as lubricant and CLD-20 is used as disintegrant at 2.5, 5, 7.5, 10% concentrations. For the purpose of comparison, tablets are also prepared with marketed disintegrants such as corn starch and croscarmellose. A typical tablet formulation is shown in Table 2a. The formulated tablets are compressed at two different compressional strength to give tablets with hardness of 6-8 kg and 8-10 kg. These tablets are evaluated for disintegration time by USP method. Tablets prepared using CLD-20 in concentration range 2.5-10% showed disintegration time of 0.4-0.6 minutes at 6-8 kg hardness and 0.5-3.3 minutes at hardness of 8-10 kgs respectively. A comparison of disintegrating time with other disintegrants indicates that the cross-linked dextrin (CLD-20) is superior to cornstarch by about 14 times, and about 5 times to superdisintegrant crosscarmellose at 2.5% disintegrant concentration respectively. The fast disintegration time exhibited at low concentration of CLD-20 is comparable superdinsintegrants. Hence, cross-linked dextrins could be categorized as superdinsintegrant. Data of disintegration time of tablets formulated using CLD-20 with 2.5-10% concentration at compressional strength of 6-8 and 8- 10 are shown in Table 2b. Similarly, tablets are prepared by direct compression method also. The tablet formulation is composed of 2.5-10% of CLD-20 as a disintegrant, Avicel PH 102 as a binder, magnesium stearate as a lubricant and dry dicalcium phosphate as a diluent and folic acid as the drug substance. The tablet formulation is shown in Table 3a. Tablet granules are compressed at two different compressional strength to give tablets with hardness of 6-8 and 8-10 Kg. Table 3b shows the disintegration time of the various tablets.

Evaluation of Toxicity

In order to evaluate the toxicity of cross-linked dextrin, the compound was fed orally to mice at 100, 500, 1000, 2000mg/kg mice and observed for behavior for 4h and mortality for 72h.

Example!

Synthesis of Cross-linking of Dextrin (CLD-20) [PCT/IN2007/000519, date of filing 05/11/07]

To a solution of 3.1 N sodium hydroxide in water (50 ml), dextrin (50 g), sodium borohydride(0.75 g), toluene (125 ml), span 80 (3.75 g), epichlorohydrin (1Og) were added and stirred at 70⁰C for about 5h. Initially the reaction mixture was homogenous solution. As the cross-linking takes place the reaction mixture turns into suspension. After heating for 5h the reaction mixture was cooled to room temperature, the water was added and pH of the reaction mixture adjusted to 6.5 using 2N hydrochloric acid. The precipitated product was initially washed with water and then with acetone. The product was dried at 45⁰C under vacuum for 6-8h. Similarly 5-50% cross-linked dextrins were synthesized by taking 2.5-25% epichlorohydrin. 5-15% cross-linked dextrins could not isolated by precipitation from water, as these were soluble in water and hence were isolated by lyophilization of reaction mixture. Example 2

Determination of Swelling Capacity

One gram cross-linked dextrins were added into a stoppered 50 ml measuring cylinder containing 40 ml water. Shaken gentle three time for 30 seconds, and water added till 50 ml then allowed to stand for 240 minutes. Volume occupied by cross-linked dextrins was noted at 15, 30, 60 and 240 minutes.

Table 1: Swelling Capacity of Epichlorohydrin Cross-linked Dextrins

Example 3

Evaluation of Disintegrating Property of Cross-Linked Dextrins in Tablets

Prepared by Wet Granulation Technique

Paracetamol (drug), dicalcium phosphate (diluent), CLD-20, starch paste (binder) were mixed to give granules. The granules were dried and milled then mixed with magnesium strearate (lubricant) and compressed into tablets at two different compressional forces to give tablets with harness of 6-8 kg and 8-10 kg. The tablets were evaluated for disintegration time according to USP protocol. The composition of 250 mg tablet is shown in Table 2a and disintegration data are shown in Table 2b. For comparison purpose tablets were also made using marketed disintegrants corn starch, crosscarmellose.

Table 2a: Tablet Formulation by Wet Granulation Method

Table 2b: Disintegration Test Results of Tablets Prepared by Wet Granulation Method

Example 4

Evaluation of Disintegrating Property of Cross-Linked Dextrins in Tablet

Preparation by Direct Compression Method

Folic acid (drug), dicalcium phosphate (diluent), CLD-20, starch paste (binder) were mixed, compressed and milled to give granules. The granules then mixed with magnesium strearate (lubricant) and compressed into tablets at two different compressional forces to give tablets with harness of 6-8 kg and 8-10 kg. The tablets were evaluated for disintegration time according to USP protocol. The composition of a typical 250 mg tablet is shown in table 3a and disintegration data are shown in table 3b

Table 3a: Tablet formulation by Direct Compression method

Table 3b: Disintegration Test Results of Tablets Prepared by Direct Compression Method

Example 5

Acute Toxicity Study

Swiss albino mice weighing 25-30gm were divided into two groups of six animals each. CLD-20 was suspended in normal saline and fed orally to mice at a dose of 100, 500, 1000, 2000mg/kg body weight. The negative control animals were fed with normal saline. The animals were observed for behavioral changes during the first 4 hours and mortality if any for 72 hours.

Claims

We Claim:

1) A cross-linked dextrin (CLD) as a pharmaceutical excipient in various pharmaceutical formulations, where in the swelling property of CLD is an important attribute in developing such formulations.

2) A CLD in claim 1 is prepared from dextrin and cross-linking agents such as, epichlorohydrin, bis-epoxypropylether, ethylene glycol-bis-epoxy propyl ether, sodium trimetaphosphate (STMP), adipic-acetic anhydride, phosphorous oxychloride, formaldehyde, diepoxides, vinylcyclohexene dioxide or butadiene dioxide.

3) A CLD in claim 2, wherein dextrin is preferably cross-linked with epichlorohydrin and the degree of cross-linking is from 1-50%.

_*

4) A CLD in claim 1 after cross-linking exhibits swelling property in aqueous environment. The swelling capacity based volume gain for CLD is between 2- 15times.

5) A cross-linked dextrin in claim 1 is used as a tablet disintegrating agent and use of such excipient in wet, dry, and directly compressible tablet formulations for pharmaceutical use.

6) A tablet prepared using CLD as disintegrating agent as in claim 5, wherein dextrin is preferably cross-linked with epichlorohydrin.

7) A tablet prepared using CLD as the disintegrating agent as in claim 5, wherein the degree of cross-linking is from 1-50%.

8) A tablet formulation prepared using disintegrating agent as in claim 5, wherein the amount of disintegrating agent concentration to the total weight of tablet is 0.5 to 20% by weight.

9) A tablet formulation prepared using CLD as disintegrating agent as in claim 5, wherein the amount of disintegrating agent concentration to the total weight of tablet is 0.5 to 20% by weight and is prepared by wet granulation method. 10) A tablet formulation prepared using CLD as disintegrating agent as in claim 5, wherein the amount of disintegrating agent concentration to the total weight of tablet is 0.5 to 20% by weight and is prepared by direct compression method.

11) A cross-linked dextrin as in claim 1, useful for pharmaceutical or non- pharmaceutical formulations wherein swellable materials are employed.