Title of Invention

A PHARMACEUTICAL COMPOSITION COMPRISING MELOXICAM GRANULATE

Abstract

The invention relates to the enhancement of dissolution of hydrophobic or water insoluble or poorly soluble or insoluble drugs by the application of melt granulation, physical mixture and solid dispersion techniques wherein the agents used for granulation are nonionic hydrophilic surfactants such as polyoxyl 20 cetyl ether and polyoxyl 40 stearate. Granules thus obtained can be formulated as various conventional and novel pharmaceutical dosage forms with enhanced dissolution of said drugs.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "Dissolution enhancement of hydrophobic drugs using surfactants" 2. APPLICANT (a) NAME: Chaudhari, Pravin Digambar (b) NATIONALITY: Indian national (c) ADDRESS: Al/303 Tushar Residency,Rahatni- Jagtap Dairy Road,Pimpale Saudagar Pune-411027 Maharashtra, India (a) NAME: Sharma, Dr. Pramodkumar (b) NATIONALITY: Indian national (c) ADDRESS: 595 A/3 Mehrauli, New Delhi-30, India (a) NAME: Bhagat, Hiren Dineshchandra (b) NATIONALITY: Indian national (c) ADDRESS: 27, Shrenik Park Society, Behind Navyug College, Rander Road Surat- 395009, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention Technical field of the invention: The instant invention relates to the techniques and formulations employed to enhance the dissolution of hydrophobic or water insoluble drugs. More particularly, the invention relates to the use of non-ionic hydrophilic surfactants and various granulation techniques for improving the dissolution of said hydrophobic drugs and thus their absorption rate. Background and prior art: Drugs are broadly classified depending on their solubility profiles as soluble, very soluble, poorly soluble and insoluble drugs. Many drugs across many pharmacological classes fall under the category of poorly soluble and insoluble drugs. Some of these drugs most commonly used in various therapies include non-steroidal anti-inflammatory drugs(NSAIDs) such as piroxicam, meloxicam, nimesulide, ibuprofen, antibacterials such as Salbactum, antibiotics such as ceftriaxone from the cephalosporin group, hypoglycemics including gliclazide, glipizide and such like. The rate and extent of dissolution of drugs from any dosage form determines the rate and extent of absorption of the drug and thus its efficacy and duration of pharmacological effect. Absorption is a primary focus in drug development and medicinal chemistry, since the drug must be absorbed before any medicinal effect can take place. Moreover, the drug's pharmacokinetic profile can be easily and significantly changed by adjusting factors that affect absorption. While the drug is already dissolved in liquid dosage forms and therefore immediately absorbed, for solid dosage forms the formulating pharmacist has to employ several techniques to enhance dissolution rate of drugs. Some of the established techniques include altering the surface area of the solid by altering the particle size by micronisation, by choosing a suitable polymorph of a compound or by using soluble salts of the compound. Also, coatings on a tablet may act as a barrier to reduce the rate of dissolution. For example, enteric coatings are applied on tablets so that the tablet disintegrates only in the basic medium of the intestine, not the acidic environment of the stomach, thus preventing poor gastric absorption problems associated with some drugs. 2 While these techniques are applications of the various physical, chemical and physico-chemical properties of the drugs, the formulating pharmacist has designed and developed many formulations that meet the challenge of improving dissolution. US 6284269 to Struengmann claims pharmaceutical composition comprising meloxicam as active ingredient, a cyclodextrin, a facultative oligosaccharide other than cyclodextrin, a facultative polysaccharide, one or more pharmaceutically acceptable additives selected from the group consisting of surfactants, hydrotropic agents, alkalizing agents, hydrocolloids, polymers and facultative excipients, carriers and/or auxiliary agents, obtained by co-milling, co-grinding or co-kneading meloxicam in the presence of cyclodextrin as a pharmaceutically acceptable additive for improving solubility and bioavailability. EP0179583 discloses novel anhydrous compositions comprising a poorly water-soluble drug and a surfactant having enhanced dissolution rate and solubility, useful in the treatment of patients, both human and veterinary, as well as domestically and in agriculture. Surfactants as pharmaceutical excipients have a number of applications in topical pharmaceutical formulations and cosmetics. They are also applied as solubilising agents, emulsifying agents, wetting agents and dispersing agents. The most widely employed surfactants include, but are not restricted to sodium lauryl sulphate, sodium desoxycholate, dioctyl sodium sulphosuccinate, polyoxyethylene polyol, polysorbate, sorbitan, polyoxyalkylated isostearyl alcohol, polyoxyethylene alkyl ether, polyoxyethylene polyol fatty acid ester, polyoxyethylene fatty glyceride and so on. Each of these compounds are available is several salt, ester and ether forms and therefore result in a huge pool of moieties available for pharmaceutical applications. It is therefore surprising that the prior art search did not reveal specific surfactant or specific group of surfactants that can improve the dissolution of hydrophobic or poorly soluble drugs thus improving their absorption and bioavailability. For a person skilled in the art of pharmaceutical formulations, it is indeed a challenge to identify the right surfactant and formulate pharmaceutical compositions of poorly soluble drugs with 3 improved and enhanced dissolution profiles, thus improving the response to the therapy rendered in specific pharmacological conditions. Objects of the invention: The object of the invention is to use specific surfactants that result in formulating pharmaceutical compositions of poorly soluble or insoluble drugs with enhanced dissolution profiles. Further object of the invention is to provide formulating techniques for the poorly soluble or insoluble drugs with the chosen surfactants to enhance their dissolution rates. Another objective of the invention is to formulate various pharmaceutical dosage forms from the drug-surfactant complex that can be readily used by a subject in need of such a therapy. Summary of the invention: The invention relates to the enhancement of dissolution of hydrophobic or water insoluble or poorly drugs by the application of melt granulation, physical mixture and solid dispersion techniques wherein the agents used for granulation are non-ionic hydrophilic surfactants such as polyoxyl 20cetyl ether and polyoxyl 40 stearate. Granules thus obtained can be formulated as various conventional and novel pharmaceutical dosage forms with enhanced dissolution of said drugs. Description of figures: Fig.l: Dissolution profiles of pure meloxicam, melt granulation, physical mixture and solid dispersion of meloxicam in polyoxyl 40 stearate. Fig.2: Dissolution profiles of pure meloxicam, melt granulation, physical mixture and solid dispersion of meloxicam in polyoxyl 20 cetyl ether. Fig.3: Dissolution profile of tablets containing meloxicam: 1) M-CAM marketed 15 mg sample, 2) Tablet contains polyoxyl 40 stearate granules and 3) Tablet contains polyoxyl 20 cetyl ether granules. 4 Fig.4: Dissolution profile of melt granules prepared with polyoxyl 40 stearate and polyoxyl 20 cetyl ether after storage at 30°C 60% RH for 3 months. Detailed description: The rate and extent of dissolution of the active ingredient from any dosage form often determines the rate and extent of absorption of the drug. In case of a poorly water soluble drug, dissolution may be the rate limiting step in the process of absorption and they absorb slowly compared to drugs of higher solubility. Therefore, it is a challenge to one skilled in the art to develop formulations with improved dissolution of the drug and thus enhance its absorption. Since solubility is a physical property of the drug, drugs with said solubility profile are found across various pharmacological classes. Drugs which are hydrophobic or insoluble or poorly soluble include, but are not limited to antibacterials, antibiotics, analgesics, antipyretics, anti-inflammatory drugs of both steroidal and nonsteroidal types, anti-parasitic, cardiovascular drugs, hypoglycemic, anticoagulants, drugs acting on the nervous system, nutritional agents, vitamins, minerals, sedatives, hypnotics, anti-convulsants, anti-epileptics, anti-parkinson's and such like. Some of the typical drugs that belong to these therapeutic groups include, piroxicam, meloxicam, nimesulide, gliclazide, glipizide, ceftriaxone, salbactam and such like. Excipients have been widely employed by the formulation development pharmacist to solve various problems such as disintegration, taste, sedimentation, odour, compressibility, density and dissolution. Dissolution of drugs from solid dosage forms such as tablets and capsules have been regularly solved by decreasing particle size, using more soluble salts or esters, employing more soluble polymorphs, coating the dosage form and such like. Similarly, surfactants have been employed as very useful ingredients to enhance dissolution. Depending on the side chains and the different class to which they belong, surfactants can be ionic or non-ionic, hydrophilic or hydrophobic. The number of compounds belonging to the class of surfactants could be several thousands of them and it is the formulating pharmacist who identifies the ones that can the enhance dissolution of poorly soluble drugs. Polyoxyl steartes are series of polyethoxylated derivatives of stearic acid. Basically, these are non-ionic surfactants which are hydrophilic in nature produced by 5 polyethoxylation of stearic acid. Polyoxyl-40 stearte is a waxy solid with a faint, bland, fat like odour, off white to light tan in colour, mainly used as emulsifying agent, solubilizing agent and wetting agent. It has low a melting point of 38° C. Due to these properties it is considered as a potential, useful hydrophilic binder in melt granulation. Polyoxyethylene alkyl ethers are series of polyoxyethylene glycol ethers of lauryl, myristyl, cetyl and sterayl alcohols, also non-ionic surfactants which are hydrophilic in nature produced by polyethoxylation of linear fatty alcohols. Polyoxyl 20 cetyl ether is solid, also with a melting point of 38° C and is classified as emulsifying agent, solubilizing agent and wetting agent. This compound is also a potential candidate for melt granulation as a hydrophilic binder Similar to the efficacious use of excipients, formulation processes and techniques have also been employed by the formulating pharmacist to solve problems associated with development and standardization of formulations. Such techniques include coating of drugs in tablet form, capsule form, on pellets, coating non-parriel seeds and such like. Other techniques include granulation process such as non-aqueous granulation, melt granulation, dry granulation, solid dispersion and such like. In the recent years, the interest in melt-granulation has increased due to the advantage of this technique as against traditional wet granulation. The melt granulation process involves the use of a substance which melts at relatively low temperature, between 50 and 80° C. This substance is added in the molten form over the substrate. Alternately when in solid form, it is heated above its melting point by hot air or by heating jacket. In both cases, after melting, the substance acts as a liquid binder, thus avoiding the use of organic or aqueous solvents. The process thus has two distinct advantages. Since organic solvents are not used, the risk of solvent residue is totally avoided. The other advantage is that the process consumes less time and energy, since the absence of an aqueous solvent negates the necessity of undergoing the drying step. By selecting a suitable binder, melt granulation can be used either to prepare controlled release or improved release granules. A great number of hydrophobic excipients have been employed in preparing controlled release granules, while polyethylene glycols can be used as hydrophilic binders. 6 Other techniques include preparing physical mixture and solid dispersion. In physical mixture, the drug is simply mixed with the surfactant and a diluent is optionally added. A simple mixing equipment is employed for the process. The solid dispersion is prepared by fusion; surfactant is melted and the drug is added. The mixture is stirred and cooled at room temperature. The solid sample is then pulverized, sieved and stored in the dessicator at 25°C. In the instant invention, non-ionic surfactants, polyoxyl-40 stearate and polyoxyl 20 cetyl ether have been employed as non-ionic surfactants that will enhance and improve the dissolution of poorly soluble hydrophobic drugs and optionally as hydrophilic binders. The drugs that fall under this category have dosages ranging from a few micrograms to about a gram. The non-ionic surfactants are used in ranges of 5-40%w/w of the formulation to exert their effect as dissolution rate enhancers and optionally as hydrophilic binders. Diluents/fillers for such formulation were selected from the group comprising starch, microcrystalline cellulose, various grades of lactose, different salts of calcium phosphate and such like. The preferred diluent in the instant invention is starlac. Starlac is a mixture of starch and lactose and is optionally also employed as binder in the range of 0-95%w/w of the formulation. The dissolution study was carried out on the granulate as against the drug and tablet prepared from said granulate using USP type II dissolution apparatus. The dissolution medium consisted of phosphate buffer pH 7.4 maintained at 37 ±0.5°C. Data obtained from the dissolution studies were analyzed using PCP Disso software. Substantial improvement in dissolution in the instant invention was observed as emulated in the examples. (Figuresl, 2 and 3) For stability studies, about 200mg of each of pure drug, melt granulation, solid dispersion and physical mixture were weighed into a glass vial. The samples were monitored up to three months at 30 °C/ 60% RH. Periodically, samples were removed and characterized by dissolution rate measurement along with presence of crystallinity and found to be compliant. (Figure 4) 7 The granulate thus obtained was used to formulate various pharmaceutical compositions that can be administered by routes including, but not limited to oral, nasal, ophthalmic, sub-lingual, chewable, dermal, parenteral, vaginal, rectal and such like. Dosage forms include tablet, coated tablets, uncoated tablets, immediate release dosage forms, sustained/controlled/delayed release dosage forms, chewable dosage forms, capsules, granules, dry syrup, sachets, oral liquids, external liquids, pastes, creams, ointments, injectables, sprays, patches and such like. To formulate such dosage forms, conventionally acceptable pharmaceutical excipients were employed such as binders, diluents, disintegrants, anti-adherents, polymers, colours, solvents, co-solvents, flavours, masking agents, complexing agents, anti-caking agents, other surfactants, vehicles and such like. Examples Example 1 Meloxicam [4-hydroxy-2 methyl-N-(5-methyl-2-thiaolyl)-2H-l, 2 benzothiazine-3- carboxamide 1, 1-dioxide] is a non steroidal anti-inflammatory drug (NSAID) used to treat rheumatoid arthritis, osteoarthritis and other joint pains. It is a hydrophobic drug and is a classic representative of this class of drugs. Meloxicam was granulated by the melt granulation, preparation of physical mixture and solid dispersion techniques Preparation of granules: Melt granulation The granules were prepared by addition of the molten polyoxyl-40 stearate or polyoxyl 20 cetyl ether to the physical mixture of drug and filler. The preferred embodiment comprised meloxicam 10%w/w, polyoxyl-40 stearate or polyoxyl 20 cetyl ether 25%w/w and starlac 65% w/w. The drug and diluent were mixed in the mortar for 15min; then the mixture was heated to 50°C on hot plate then molten polyoxyl-40 stearate or polyoxyl 20 cetyl ether was added to prepare granules. The granulaition time was 5 min. At the end of the granulation process, granules were cooled at room temperature by spreading them out on trays, collected and passed through 40# sieve. 8 Preparation of physical mixture: The physical mixture was prepared by simply mixing meloxicam, polyoxyl-40 stearate or polyoxyl 20 cetyl ether and starlac in a mortar with a pestle for 15 mins. Preparation of solid dispersion: The solid dispersion was prepared by fusion; polyoxyl-40 stearate or polyoxyl 20 cetyl ether was melted and meloxicam was added. The mixture was stirred for 5 min at 60°C1 and then cooled on aluminum foil at room temperature. The solid sample was then pulverized in the mortar, sieved and stored in the dessicator at 25°C. Preparation of tablet: Melt granules equivalent to 15mg of meloxicam with Ac-Disol 5% were geometrically mixed and lubricated with 1 % w/w magnesium stearate. Formulation was passed through a no.30 mesh sieve and was directly compressed using 12 station tablet machine. The tablets complied with all physical parameters for characterization of tablets such as hardness, friability, disintegration, dimensions and such like. Example 2 In Vitro Dissolution Studies: The dissolution of meloxicam alone, meloxicam from the melt granulation (MG), meloxicam from the physical mixture (PM) and meloxicam from the solid dispersion (SD) were determined using USP type II dissolution apparatus. The dissolution medium consisted of phosphate buffer pH 7.4 maintained at 37 ±0.5°C. Samples equivalent to 15mg of meloxicam was added to 900ml of dissolution medium in a 1000 ml cylindrical beaker. The paddle speed was 100 rpm. 10ml samples were withdrawn at suitable time intervals of 5, 10 and 15 minutes, over a period of 90 minutes. The same volume of preheated dissolution medium was infused into the medium after each sample was drawn in order to maintain a constant volume of the dissolution medium throughout the test. The samples were filtered using whatmann filterpaper (41) and the meloxicam content was determined spectrophotometrically at A,max 363 nm using Shimadzu UV-1700 spectrophotometer. Data was analyzed by PCP-Disso software 9 The dissolution profile of pure meloxicam is very low; in fact the percentage of drug dissolved in 50 min was 38.5% and formation of physical mixture improved this value. On the contrary, both the melt granules and the solid dispersion showed a substantial increase in the dissolution of drug compared to pure meloxicam. There was 80.2% and 90.40% of drug dissolved in the first 15 minutes in melt granules and solid dispersion prepared with polyoxyl-40 stearate respectively, whereas dissolution profile of samples containing polyoxyl 20 cetyl ether showed 66.06%, 84.22% and 90.53% release of drug after 30 minutes for melt granulation, physical mixture and solid dispersion respectively. The enhancement of dissolution can be attributed to the solubilization effect of polyoxyl-40 stearate/ polyoxyl 20 cetyl ether, improved wettability and dispersibility of the drug from the melt granules as well as solid dispersion. The sample mixture of the components also improved the release of meloxicam suggesting that melt granulation using polyoxyl-40 stearate /polyoxyl 20 cetyl ether could be a useful method to improve the dissolution rate of meloxicam. Dissolution studies were preformed for tablets in triplicates. Dissolution was performed in 900 ml phosphate butter (pH 7.4) using USP XXIV type II dissolution apparatus. The dissolution medium was stirred at 100 rpm and maintained at 37. ±0.5°C. Drug release was determined using UV spectrophotometer at 363.5 nm. For comparison a commercial tablet M-CAM was also studied. Data obtained from the dissolution studies was analyzed using PCP Disso software. Example 3: Stability Studies: For stability studies about 200mg of each of pure drug, melt granulation, solid dispersion and physical mixture was weighed into a glass vial. The samples were monitored up to three months at 30 °C/ 60% RH. Periodically, samples were removed and characterized by dissolution rate measurement along with presence of crystallinity. The dissolution profiles of three months stored melt granules were similar to freshly prepared ones. Moreover, no difference in the x-ray graph was found proving the stability of the composition of the invention 10 Many changes, modifications, variations and applications of the subject invention will become apparent to those skilled in the art after consideration of the specification. All such changes, modifications, alterations and other uses and applications that do not depart from the spirit and scope of the invention are deemed to be covered by the invention. Dated this 19th day of April, 2007 11

Documents:

761-mum-2007-abstract(21-4-2008).pdf

761-MUM-2007-CLAIMS(AMENDED)-(20-1-2014).pdf

761-MUM-2007-CLAIMS(AMENDED)-(23-6-2014).pdf

761-mum-2007-claims(complete)-(21-4-2008).pdf

761-MUM-2007-CLAIMS(MARKED COPY)-(20-1-2014).pdf

761-MUM-2007-CLAIMS(MARKED COPY)-(23-6-2014).pdf

761-MUM-2007-Claims-021214.pdf

761-MUM-2007-CORRESPONDENCE(15-11-2010).pdf

761-mum-2007-correspondence(21-4-2008).pdf

761-MUM-2007-CORRESPONDENCE(23-5-2014).pdf

761-mum-2007-correspondence-received.pdf

761-mum-2007-description (provisional).pdf

761-mum-2007-description(complete)-(21-4-2008).pdf

761-mum-2007-drawing(21-4-2008).pdf

761-mum-2007-drawings.pdf

761-mum-2007-form 1(9-7-2007).pdf

761-MUM-2007-FORM 18(15-11-2010).pdf

761-mum-2007-form 2(complete)-(21-4-2008).pdf

761-mum-2007-form 2(title page)-(complete)-(21-4-2008).pdf

761-mum-2007-form 2(title page)-(provisional)-(19-4-2007).pdf

761-mum-2007-form 26(9-7-2007).pdf

761-mum-2007-form 5(21-4-2008).pdf

761-mum-2007-form-1.pdf

761-mum-2007-form-2.doc

761-mum-2007-form-2.pdf

761-mum-2007-form-26.pdf

761-mum-2007-form-3.pdf

761-MUM-2007-MARKED COPY(02-12-2014).pdf

761-MUM-2007-OTHERS-021214.pdf

761-MUM-2007-REPLY TO EXAMINATION REPORT(20-1-2014).pdf

761-MUM-2007-REPLY TO HEARING(23-6-2014).pdf

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