Title of Invention

A METHOD OF MAKING A SUSTAINED RELEASE HOT MELT EXTRUDATES COMPOSITION

Abstract

Sustained release hot melt extrudates using hot melt extrusion suitable for oral and ophthalmic drug delivery systems comprising at least one active pharmaceutical ingredient, at least one plasticizer and hydroxypropyl cellulose is discussed. The hot melt extrudates are used for oral and ocular drug delivery systems. These compositions are prepared by blending in an extruder or charging premixed to the extruder, active pharmaceutical ingredient, plasticizer and hydroxypropyl cellulose; heating the said blend; extruding the mixture as a long extrudate. The hot melt extrudates with other pharmaceutically acceptable excipients can be processed to granules, pellets, grains, minitablets, tablets or filled in capsules for oral administration or directly instilled in the eye for ocular drug delivery system.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: " Sustained release extrudates using melt extrusion technology" 2. APPLICANT (a) NAME: AMIN PURNIMA DHANRAJ (b) Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, University of Mumbai, Nathalal Parikh Marg, Mumbai - 400 019, Maharashtra, India. (c) Indian National 3.PREAMBLE TO THE DESCRIPTIONThe following specification particularly describes the invention Sustained release extrudates using melt extrusion technology Technical field: This invention relates to sustained release extrudates of active pharmaceutical ingredients in polymeric matrix using melt extrusion technology and method of their production. Background and prior art It is well known fact that certain ailments require multiple doses of a particular drug, in which case the blood levels of a drug need to be maintained above its minimum effective level and below its minimum toxic level in order to obtain the desired therapeutic effects. When the blood levels of a drug are in optimum range, the drug is eliminated from the body at a particular rate. A controlled drug delivery system is usually designed to deliver the drug at particular rate to maintain safe and effective blood levels for a period as long as the system continues to deliver the drug at this rate. Controlled drug delivery results in substantially constant blood levels of the active ingredient as compared to the multiple doses of quick releasing conventional dosage forms, which results in uncontrolled fluctuations of blood levels. Since the controlled drug delivery results in optimum therapy, with additional advantages such as reduction in frequency of dosing and minimizing the side effects, considerable efforts have been made in the last decades to develop new drug delivery systems which give viable and therapeutically effective treatment to the patients. Consequently, current trends in pharmaceutical research leads to the development of large number of controlled drug delivery systems with different kinds of release mechanisms which deliver the drug at designed rate. These controlled drug delivery systems are based on different modes of operation and have been variously named, for example, as dissolution controlled systems, diffusion controlled systems, ion-exchange resins, osmotically controlled systems, erodible matrix systems, pH-independent formulations, swelling controlled systems, and the like. Classical processes for producing solid pharmaceutical forms, especially tablets, are carried out batch wise and comprise a plurality of stages. A considerably simpler continuous process for producing solid pharmaceutical forms has been known for some time and entails extruding a solvent-free melt of a polymeric binder containing active ingredients, and shaping the extrudate to the required dosage form. (US Patent Nos. 4,801,460, 4,880,585, 5,073,379 and EP 0358105, EP 240904 and EP240906) US Patent No. 4,957,681 describes continuous process for preparing pharmaceutical mixtures having at least two components which are continuously metered. The process includes continuously metering the individual components of the pharmaceutical mixture at a rate of at least 50 g/h on electronic differential metering balances having a metering accuracy of at least ±5% within time intervals of less than one minute and, additionally, having screw conveyors, thereby obtaining a substantially uniformly metered mixture; and shaping the mixture. This method is focused on electronic differential metering balances having screw conveyors to achieve uniformly mixed mixture and does not disclose preparation of sustained release pharmaceutical formulations. US Patent Nos. 6,423,256 describes the process for producing solid dosage forms, consisting of a plastic mixture of at least one pharmacologically acceptable polymeric binder with a K value of more than 75, at least one pharmaceutical active ingredient and, where appropriate, pharmaceutical additive is prepared. The plastic mixture is shaped to the required dosage form under conditions of temperature and shear energy input such that the reduction in molecular weight of the polymeric binder, expressed as the difference in the K value, is less than 15 wherein the polymeric binder is a homo- or copolymer of vinylpyrrolidone. US Patent Nos. 6,528,089 describes the process for producing solid pharmaceutical, sustained release dosage forms by mixing at least one polymeric binder, at least one pharmaceutical active ingredient and, where appropriate, conventional additives to form a plastic mixture, and shaping, wherein the polymeric binder used is a copolymer of an N-vinyllactam. US Patent Nos. 7,022,344 describes the process for producing a solid dosage form by mixing at least one polymer binder, at least one active ingredient and optionally conventional additives to form a plastic mixture, and shaping the plastic mixture, wherein the polymeric binder is a water-swellable graft copolymer which is obtained by free radical initiated polymerization of monomers and grafting bases. The above mentioned three patents (US Patent Nos. 6,423,256, 6,528,089, 7,022,344) relates to the synthesis of a polymer that can be melt extruded along with active pharmaceutical agents resulting in a sustained release formulation. However our invention is related to hydrophilic Polymer (Hydroxypropyl Cellulose) EP 0177893 describes a method of making thermoformable sustained release matrix for the prolonged release of an active organic material, comprising of a thermoplastic water-soluble gel having a water-soluble Hydroxypropyl methylcellulose homogeneously dispersed in a major amount of a plasticizer for said Hydroxypropyl methylcellulose and an effective amount of an active organic material dispersed in said gel. EP 0598606 relates to compositions (for topical or transdermal drug delivery) of a thermoplastic water-soluble polymer; a water-soluble polymer derived from a carboxylic acid or a pharmaceutically acceptable salt thereof; and a plasticizer. The thermoplastic water-soluble polymer may be poly(ethylene oxide), and the compositions can be prepared as hot-melts. US Patent No 6,488,963 relates to a non-film controlled release pharmaceutical formulation comprising of an effective amount of a therapeutic compound and a high molecular weight poly(ethylene oxide), having a molecular weight of about 1,000,000 to about 10,000,000 Daltons, in a ratio of poly(ethylene oxide) to therapeutic compound from about 99.99. .01 weight percent to about 50:50 weight percent. US Patent No 6,805,881 describes a process for the production of an orally administrable multiple-unit sustained-release pharmaceutical composition having controlled agitation-independent release, consisting essentially of the steps of (a) combining Hydroxypropyl cellulose polymer in an amount from 40 to 95% by weight with a pharmaceutical^ active compound and optionally with one or more pharmaceutical^ acceptable additional polymers and/or excipients which do not contribute significantly to a sustained-release effect. The said mixture is converted into particles having a diameter of 0.2 to 3.0 mm and incorporated said particles into an orally administrable multi-unit sustained release dosage form. The said polymer has a molecular weight of 250000 to 1200000 and a molar degree of substitution of at least 3. The invention describes the process without using plasticizer and has many limitations. We have found that the use of plasticizer can reduce the processing temperature and can thus prevent the possible degradation of active pharmaceutical ingredients mainly thermolabile actives. Also the extrudates produced by melt extrusion using Hydroxypropyl cellulose without a plasticizer produce a rough surface. Such extrudates have a large surface area exposed and can thus release the drug at a faster rate or requires higher percentage of Hydroxypropyl cellulose to achieve the desired release profile. The same release profile can be achieved using lesser concentration of Hydroxypropyl cellulose and plasticizer. Thus use of plasticizer allows incorporation of higher percentage of active pharmaceutical ingredients making the process an economic feasible. Also, such smooth extrudates can also be used as ocular inserts apart from oral drug delivery systems. Melt extrusion technology has been reported for formulating sustained release dosage forms of opioid analgesics (US Patent No 6,743,442), hydrocodone analgesics (US Patent No 6,733,783), methylphenidate, an psychostimulant (US Patent No 6,673,367), and methylphenidate formulations which provide a rapid initial onset of effect and a prolonged duration of effect (US Patent No 7,083,808). However it is not obvious from the prior art that sustained release extrudates formulated using melt extrusion can comprise higher percentages of active pharmaceutical agents belonging to a wide variety of class and thus making an economical feasible process. Such sustained release extrudates can be achieved using the present invention. In the present invention sustained release extrudates are formulated whose release is controlled by various factors such as percentage of active, solubility of active and the processing temperature. Varying these parameters a desired sustained release profile can be achieved for a wide variety of actives having varying solubilities. Objective of the invention: The objective of the invention is to provide a sustained release extrudates using melt extrusion technology incorporating higher percentage of active pharmaceutical agents in the said formulation Another objective of the invention is to provide a sustained release extrudates using melt extrusion technology, which comprise wide variety of active pharmaceutical agents having varying solubilities. Another objective of the invention is to develop sustained release formulation suitable for oral and ocular drug delivery. Another object of the invention is to provide a sustained release extrudates using melt extrusion technology, which can be in various dosage forms such as extrudates, pellets, granules, grains or mini tablets. They can either fill in a hard gelatin capsule or compressed as a tablet or can also be administered as such. The extrudates can also be used as ophthalmic inserts. Another object of the invention is to provide a method of making a sustained release extrudates using melt extrusion technology, which method is economical and eco -friendly. Summary of the invention: Sustained release extrudates of active pharmaceutical ingredients using melt extrusion technology is disclosed. The sustained release extrudates essentially comprise active ingredient having varying solubilities. Optionally other pharmaceutical acceptable excipients may be added. These dosage forms are prepared by mixing drug, polymer and plasticizer; extruding them through melt extruder and the extrudates are further cut into desired size. These extrudates may be further processed to tablets or filled in hard gelatin capsules for oral administration or directly instilled in the eye for ocular drug delivery system. Description of drawings: Fig. 1 shows in vitro release profile of sustained release extrudates of Carbamazepine, Acyclovir and Idoxuridine for oral use Fig. 2 shows in vitro release profile of sustained release extrudates of Acyclovir, Idoxuridine and Gatifloxacin for ophthalmic use Detailed description According to the invention Sustained release extrudates using melt extrusion technology comprising 1 to 80%, preferably 5 to 75% by weight of at least one active pharmaceutical ingredient, 1 to 15%, preferably 2 to 8% by weight of at least one Plasticizer and 5 to 98%, preferably 17 to 93% by weight of at least one hydrophilic polymer, as a release retarding agent The Sustained release extrudates have a diameter of from 0.05 to 5 mm, preferably 0.1 to 3 mm; and a length from 0.05 to 10 mm preferably 0.1 to 6 mm. The preferred length for orally administered extrudates is 0.1 to 3 mm and that for ophthalmic inserts is 1 to 6 mm. The Sustained release extrudates can be designed for once or twice a day dosing. Sustained release extrudates according to the invention are used for oral and ocular drug delivery systems. The extrudates of the invention may optionally be further processed to granules, pellets, grains, mini tablets, tablets or filled in hard gelatin capsules for oral administration or directly instilled in the eye for ocular drug delivery system. Sustained release extrudates according to the invention are the formulations that in the USP dissolution test release not less than 80% of the active pharmaceutical ingredient within 6 to 14 hours, preferably 8 to 12 hours for a twice daily formulations and within 16 to 26 hours, preferably 20 to 24 hours for a once daily formulations. The active pharmaceutical ingredient is, for example, selected from the group having varying solubilities. The extrudates of the invention include at least one polymer. The polymer preferably is a thermoforming polymer and imparts sustained release of the active. The polymer can be selected from the class of cellulose derivatives and preferably the polymer is Hydroxypropyl cellulose. The extrudates of the invention include at least one plasticizer. The plasticizer includes all compounds capable of plasticizing said polymers. The plasticizer should be able to lower the glass transition temperature or softening point of the polymer in order to allow for lower processing temperature, extruder torque and pressure during melt extrusion process. Plasticizer also imparts advantageously physical properties such as smooth surface to the extrudates that in turn help in better control of the release. Plasticizers are selected from the group glycerin, propylene glycol, polyethylene glycol, triethyl citrate and castor oil, preferably glycerin, propylene glycol, and polyethylene glycol According to the invention there is provided a method of making sustained release extrudates using melt extrusion technology, the method comprising (i) blending in an extruder or charging premixed to the extruder, 1 to 80%, preferably 5 to 75% by weight of at least one active pharmaceutical ingredient, 1 to 15%, preferably 2 to 8% by weight of at least one Plasticizer and 5 to 98%, preferably 17 to 93% by weight of at least one hydrophilic polymer, (ii) heating the said blend to a temperature sufficient to soften the mixture and sufficient to extrude the same (iii) extruding said heated mixture as a long extrudate having a diameter of from 0.05 to 5 mm, preferably 0.1 to 3 mm; cooling said long extrudate; and dividing said strand to form non-spheroidal extrudates having a length from 0.05 to 10 mm preferably 0.1 to 6 mm; said extrudates providing a sustained release of said active agent for a time period such that not less than 80% of the active pharmaceutical ingredient is released within 6 to 14 hours, preferably 8 to 12 hours for a twice daily formulations and within 16 to 26 hours, preferably 20 to 24 hours for a once daily formulations (iv) Optionally mixing the said extrudates with other pharmaceutically acceptable excipients and processed to granules, pellets, grains, minitablets, tablets or filled in hard gelatin capsules for oral administration or directly instilled in the eye for ocular drug delivery system. These formulations are prepared by the simple, dust free and single step process, which makes it cost effective and safe for the humanity. This present invention helps in eliminating the steps of mixing, granulation, extrusion or drying. Here we have to weigh and charge the material to the extruder and we directly get the final product. The said process is thus economically viable and industrially feasible process. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of examples and for purpose of illustrative discussion of preferred embodiments of the invention. Example 1: Sustained release extrudates of Carbamazepine for oral use Ingredients Quantities Carbamazepine 66% Plasticizer 5% Hydroxypropylcellulose 28% Example 2: Sustained release extrudates of Acyclovir for ophthalmic use Ingredients Quantities Acyclovir 16.67% Plasticizer 5% Hydroxypropylcellulose 78.33 Example 3: Sustained release extrudates of Idoxuridine for ophthalmic use Ingredients Quantities Idoxuridine 3.75% Plasticizer 7.5% Hydroxypropyl cellulose 88.75% Example 4: Sustained release extrudates of Gatifloxacin for ophthalmic use Ingredients Quantities Gatifloxacin 5.0% Plasticizer 5.0% Hydroxypropyl cellulose 90.00% Example 5: Sustained release extrudates of Acyclovir for oral use Ingredients Quantities Acyclovir 50.00% Plasticizer 5.00% Hydroxypropyl cellulose 45.00% Example 6: Sustained release extrudates of Idoxuridine for oral use Ingredients Quantities Idoxuridine 50.00% Plasticizer 5.00% Hydroxypropyl cellulose 45.00% General procedure for carrying out Dissolution of the multiparticulates USP type I apparatus was used for carrying out the in vitro release studies for all the formulations. Distilled water was used as the dissolution medium. Each capsule was placed in the basket and transferred to 900 ml of dissolution medium .The temperature of the medium was maintained at 37° C ±0.5° C. The shaft was rotated at 100 rpm. Aliquots were taken at intervals and analyzed by Ultraviolet Spectrophotometric method. The in vitro release studies for ophthalmic extrudates were performed in a modified dissolution apparatus as per USP specification. The dissolution conditions were Temperature: 37 + 1°C, Horizontal amplitude: 3.8 cm, Frequency: 32 cycles/min. Each insert was tied in muslin cloth and was placed in the test tube containing 10 ml dissolution medium with the help of the hanger, in triplicates. Aliquots were withdrawn at 1,2, 4, 6, 8, 10 and 12 hours. The aliquots were suitably diluted and analysed by UV spectrophotometry. The % cumulative release of the drug was computed and graph of % cumulative release vs time was plotted. In vitro release studies of all the formulations specified in Pharmacopoeia were studied and found to be within specified limits. It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Documents:

1439-mum-2006-abstract(10-9-2007).pdf

1439-MUM-2006-ABSTRACT(29-9-2014).pdf

1439-MUM-2006-ABSTRACT(31-12-2012).pdf

1439-mum-2006-claims(10-9-2007).pdf

1439-MUM-2006-CLAIMS(AMENDED)-(31-12-2012).pdf

1439-MUM-2006-CORRESPONDENCE(14-1-2011).pdf

1439-mum-2006-correspondence(6-9-2007).pdf

1439-mum-2006-description (provisional).pdf

1439-mum-2006-description(complete)-(10-9-2007).pdf

1439-mum-2006-drawing(10-9-2007).pdf

1439-MUM-2006-DRAWING(29-9-2014).pdf

1439-MUM-2006-DRAWING(31-12-2012).pdf

1439-mum-2006-drawings.pdf

1439-mum-2006-form 18(29-4-2008).pdf

1439-mum-2006-form 2(10-9-2007).pdf

1439-mum-2006-form 2(title page)-(10-9-2007).pdf

1439-mum-2006-form 2(title page)-(7-9-2006).pdf

1439-mum-2006-form 5(6-9-2007).pdf

1439-mum-2006-form-1.pdf

1439-mum-2006-form-2.doc

1439-mum-2006-form-2.pdf

1439-mum-2006-form-3.pdf

1439-MUM-2006-MARKED COPY(29-9-2014).pdf

1439-MUM-2006-MARKED COPY(31-12-2012).pdf

1439-MUM-2006-REPLY TO EXAMINATION REPORT(31-12-2012).pdf

1439-MUM-2006-REPLY TO HEARING(29-9-2014).pdf

1439-MUM-2006-SPECIFICATION(AMENDED)-(29-9-2014).pdf

1439-MUM-2006-SPECIFICATION(AMENDED)-(31-12-2012).pdf

abstract-1.jpg