IMPROVED PROCESS FOR MANUFACTURE OF NSAIDs AND NARCOTIC ANALGESICS TABLETS

FIELD OF THE INVENTION

The present invention relates improved process for manufacture of NSAIDs and Narcoticanalgesics film-coated tablets. More particularly the present invention relates to improved process for manufacture of Ibuprofen and Codeine phosphate and its hydrates film-coated tablets.

BACKGROUND OF THE INVENTION

Non-steroidal anti-inflammatory drugs (NSAIDs) are drugs which have anti-pyretic, analgesic and anti-inflammatory actions. These are primarily used to treat inflammation, mild to moderate pain, and fever. The most common NSAIDs are currently available in the market are Ibuprofen, Aspirin, ketoprofen, Sulindac, Naproxen, Etodolac, fenoprofen, diclofenac, flubiprofen, ketorolac, piroxicam, indomethacin, mefenamic acid, meloxicam, nabumetone, oxaprozin, mecolfenamate, tolmetin, and salsalate. They can provide enough relief to make people more comfortable and to allow them to carry out their daily routines. Ibuprofen originally marketed as Brufen and is available under a variety of popular trademarks, including Motrin, Nurofen, Advil, and Nuprin; and is available as tablets, oral suspensions and topical gel forms. Chemically Ibuprofen is (RS)-2-(4-(2-methylpropyl) phenyl) propanoic acid.

The Narcotic analgesics, also termed opioids, are all derived from opium. The drugs comes under this class includes morphine, codeine, and a number of semi-synthetics including meperidine (Demerol), propoxyphen (Darvon) and others. The narcotic analgesics vary in potency, but all are effective in treatment of visceral pain when used in adequate doses. Codeine is marketed as both a single-ingredient drug and in combination preparations with the ibuprofen, aspirin and acetaminophen. These combinations provide greater pain relief than either agent alone. Codeine phosphate is available in market as tablets, syrups and injectables. Chemically codeine phosphate hemi hydrate is 7,8-Didehydro-4,5alpha-epoxy-3-methoxy-17-methylmorphinan-6alpha-ol phosphate (l:l)(salt) hemi hydrate.

AU699224 patent discloses a pharmaceutical formulation comprising ibuprofen or a pharmaceutically acceptable salt there of and codeine or a pharmaceutically acceptable there of in association with a pharmaceutically acceptable carrier where in said carrier comprises a lubricant, a disintegrant and a diluent characterized in that the lubricant is substantially free from Stearic acid and stearate ions, and is selected from hydrogenated vegetable oils.

EP068838 patent discloses a product containing flurbiprofen or C1-8 alkyl ester of pharmacologically active salt there of and a narcotic analgesic as a combination preparation is selected from morphine, hydromorphone, oxymorphone, levorphanol, methadone, meperidine, aniloridine, alphaprodine, fentanol, codeine, codone and Oxycodone for combination preparation for simultaneous or separate use in the treatment of pain.

EP159852 patent discloses a method of producing a stable, directly tabletable composition of two or more pharmaceutically active ingredients which are interactive each other. Where first active ingredient is selected from codeine phosphate and other active ingredients are selected from the group of non steroidal analgesic agents such as acetaminophen, aspirin, ibuprofen, and sodium naproxen. The method comprises blending one of the active ingredients with a binder and filler, wet granulating the mixture in the presence of a solvent, drying and sizing the granulated mixture and blending the mixture with one or more other pharmaceutically active ingredients.

EP220805 patent discloses a pharmaceutical composition in the form of a multiphase tablet comprising at least one narcotic analgesic phase containing a therapeutically effective quantity of a narcotic analgesic or an analgesically effective salt thereof and at least one non-steroidal anti-inflammatory phase containing a therapeutically effective quantity of a non-steroidal anti-inflammatory carboxylic acid or an anti inflammatory salt or ester thereof wherein the at least one narcotic analgesic phase is free from a non-steroidal anti-inflammatory carboxylic acid or salt or ester thereof, stearic acid and a stearate salt, and the at least one non-steroidal anti-inflammatory phase is free from a narcotic analgesic or salt thereof, stearic acid and a stearate salt, and further wherein both the at least one narcotic analgesic phase comprises a morphinan-6-ol or a morphinan-6-one derivative, preferably morphine, ethyl morphine, hydromorphone, hydroquinone, dihydrocodeine or codeine and the at least one non-steroidal anti-inflammatory phase contain at least one self-lubricating, compression aid, preferably at least one self lubricating, direct compression aid.

EP274845 patent discloses a solid composition comprising ibuprofen or a pharmaceutically acceptable salt thereof and codeine or a pharmaceutically acceptable salt thereof together with a sufficient amount of an insoluble salt of carboxy methylcellulose is calcium carboxymethylcellulose to prevent discoloration of the composition. This patent discloses compositions of uncoated tablets with carboxy methyl cellulose and there is no coating is applied to the tablets.

EP388125 patent discloses the use of ibuprofen or a pharmaceutically acceptable salt thereof; and codeine or a pharmaceutically acceptable acid addition salt thereof; for the manufacture of a medicament for the treatment of acute pain in humans; characterized in that the medicament is for administration to an adult human in a single dose comprising from 100 to 600mg (expressed as the weight of the free acid) of ibuprofen or a pharmaceutically acceptable salt thereof, and from 12 to 40mg (expressed as the weight of the free base) of codeine or a pharmaceutically acceptable acid addition salt thereof.

EP535841 patent discloses the use of ibuprofen or a pharmaceutically acceptable salt thereof and codeine or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of pain of chronic medical conditions, the ratio of ibuprofen to codeine being in the range 15:1 to 25:1.

EP0777477 patent discloses a pharmaceutical formulation comprising ibuprofen or a pharmaceutically-acceptable salt thereof and codeine or a pharmaceutically-acceptable salt thereof in association with a pharmaceutically acceptable carrier wherein said carrier comprises a lubricant, a disintegrant from cross-linked polyvinylpyrrolidone, croscarmellose sodium and sodium starch glycolate and mixtures thereof; a diluent from Cellactose [registered trademark], microcrystalline cellulose and carboxy methyl cellulose and mixtures thereof; Characterized in that the lubricant is substantially free from stearic acid and stearate ions, and is selected from hydrogenated vegetable oils such as hydrogenated soybean oil and hydrogenated castor oils, and mixtures thereof. This patent discloses use of vegetable oils as lubricant for preventing discoloration of tablets.

US 20110293716 patent discloses a new formulation consists of ibuprofen and codeine in the form of a tablet, which comprises L-leucine in a concentration ranging between 4%-15% as a lubricant, in order to prevent the formulation mixture from adhering to the punches and to other elements of the compression machine during the compression process. Additionally comprises 0.5%-5.0% of talc and 30-80% of silicified micro crystalline cellulose. The core tablet is coated with a composition that contains 30% dispersion of copolymer of methacrylic acid and ethyl acrylate (1:1).

US 20110144144 patent discloses a pharmaceutical tablet composition comprising ibuprofen, a narcotic analgesic, colloidal silicon dioxide, a filler selected from the group of microcrystalline cellulose and a powdered cellulose; a disintegrant selected from croscarmellose sodium, crospovidone, and sodium starch glycolate; a binder consisting of an akyl hydroxy methylcellulose; a starch; and a lubricant in a single phase, wherein the granule is formed by a wet granulation process.

All the above prior-arts disclose various compositions for the combination of ibuprofen and codeine phosphate and also disclose improved formulation compositions for preventing discoloration/splitting/cracking of tablets during storage/shelf-life of the product using carboxy methyl cellulose/vegetable oils. As there is common problem with the combination of ibuprofen and codeine phosphate as this combination of product prone to discoloration/cracking during storage, hence there is need to improve and preparation of stable formulation which is resist for discoloration as well as cracking. The present inventors have developed improved process for the manufacture of stable film-coated tablets which comprises, coating of core tablets by using aqueous coating technology.

SUMMARY OF THE INVENTION

The present invention provides improved process for the manufacture of NSAIDs and narcotic analgesics stable film-coated tablet dosage form, wherein the process comprises coating of uncoated tablets by aqueous coating process.

DETAILED DESCRIPTION OF THE INVENTION

The main embodiment of the present invention is improved process for the manufacture of stable film-coated tablet dosage form of NSAIDs and narcotic analgesics, wherein the process comprises aqueous coating of uncoated tablets.

The uncoated tablets are prepared by techniques known in the industry like direct compression, wet granulation or dry granulation.

Direct compression technique generally involves blending of all ingredients in a blender for suitable time till to achieve blend uniformity and compress into tablets of suitable size and shape.

Wet granulation technique generally involves utilization of solvents for preparation of granules. This process generally had the steps of mixing one or both actives with diluent, optionally disintegrant, optionally binder in a blender and granulating this mixture either by aqueous or non aqueous granulation, drying of granulate, optionally sieving of dried granules and blending dried granules with lubricant, optionally glidant, optionally diluent, disintegrant and active.

Suitable solvents used according to the present invention for preparation of wet granulation are selected from water, isopropyl alcohol, methylene chloride and combinations thereof.

Dry granulation is another technique where it doesn't use any solvents for preparation of granules. This process generally had the steps of mixing one or both actives with diluent, optionally disintegrant, binder in a blender. Slugging and de-slugging the blend and blended with lubricant, optionally glidants, optionally disintegrant, optionally diluent and optionally active.

"Aqueous" means which is substantially free of any organic solvents.

Aqueous coating solution is prepared by dispersing film formers, opacifiers, plasticizers and/or coloring agents or readymade coating materials like Opadry® compositions in purified water. Then coating is applied on uncoated tablets using the aqueous coating solution and drying of tablets.

Suitable film-formers used according to the present invention are selected from hydroxy propyl methylcellulose, hydroxy propyl cellulose, polyvinyl alcohol, ethyl cellulose and combinations thereof.

The film-coating as described in the present invention may be non-functional or functional coating.

Suitable colorants according to the present invention are selected from Opadry white, brilliant blue and quinoline yellow.

The uncoated tablet of the present invention may be immediate release or modified release.

The uncoated tablet of the present invention contains one or more pharmaceutical acceptable excipients.

One or more pharmaceutically acceptable excipients are selected from diluents, disintegrants, binders, glidants, lubricants, colorants and release modifying agents.
Diluents are inactive ingredients that are added to tablets and capsules in addition to the active drug. A good diluent must be inert, compatible with the other components of the formulation, non-hygroscopic, relatively cheap, compatible, and preferably tasteless or pleasant tasting. Suitable diluents according to the present invention are selected from micro crystalline cellulose, lactose, sucrose, glucose, mannitol, sorbitol and dibasic calcium phosphate.

Disintegrants are agents added to tablet formulation to promote the breakup of the tablet into the small fragments in an aqueous environment thereby increasing the available surface area and promoting a more rapid release of the drug substance. Suitable disintegrants according to the present invention are selected from carboxy methyl cellulose calcium, starch, sodium starch glycolate, crospovidone and alginic acid.

Binders are agents which hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength, and give volume to low active dose tablets. Binders are classified into two types i) solution binders ii) dry binders. Solution binders are dissolved in solvent like water or alcohol in wet granulation processes. Suitable binders according to the present invention are selected from Povidone, gelatin, cellulose, cellulose derivatives, starch and sucrose. Dry binders are added to the powder blend, either after a wet granulation step, or as part of a direct powder compression (DC) formula. Examples include cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol.

Glidants are agents these are used to promote powder flow by reducing inter particle friction and cohesion. Suitable glidants according to the present invention are selected from colloidal anhydrous silica, talc and fumed silica.

Lubricants are agents which prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low friction between the solid and die wall. Suitable lubricants according to the present invention are selected from stearic acid, magnesium stearate, calcium stearate and talc.

Colorants are agents used to impart a distinctive appearance to the pharmaceutical dosage forms. Coloring may require to increase the aesthetic appearance or to prolong the stability or to produce standard preparations or identification of a particular formulation.

Suitable colorants or readymade coating materials according to the present invention are selected from Opadry white, brilliant blue and quinoline yellow.

Release modifying agents are used to modify the drug release from the dosage form. Suitable release modifying agents may be selected from hydroxyproppyl methylcellulose, hydroxy propyl cellulose, ethyl cellulose, methyl cellulose, carboxy propyl methyl cellulose, polyethylene oxide, xanthan gum, guar gum, methacrylates, polyvinyl pyrrolidone, polyvinyl chloride, polypropylene and gelatin.

NSAIDs are selected from Ibuprofen, Aspirin, ketoprofen, Sulindac, Naproxen, Etodolac, fenoprofen, diclofenac, flubiprofen, ketorolac, piroxicam, indomethacin, mefenamic acid, meloxicam, nabumetone, oxaprozin, mecolfenamate, tolmetin, and salsalate. and their pharmaceutically acceptable salts, solvates, hydrates there of. More preferably NSAID is selected from Ibuprofen and its pharmaceutically acceptable salts thereof.

Narcotic analgesics are selected from codeine, morphine, meperidine, propoxyphen and their pharmaceutically acceptable salts, solvates, hydrates thereof. More preferably narcotic analgesic is selected from codeine and its pharmaceutically acceptable salts, solvates, hydrates thereof. Still more preferred narcotic analgesic is codeine phosphate hemi hydrate or codeine phosphate.

The present invention is further illustrated by the following non limiting examples:

Example 1: Blend is prepared by aqueous granulation and film-coating is by aqueous coating process

Example 2: Blend is prepared by aqueous granulation and film-coating is by non-aqueous coating process

Example 3: Blend is prepared by Non-Aqueous granulation and film-coating is by aqueous coating process

Example 4: Blend is prepared by Non-Aqueous granulation and film-coating is by non-aqueous coating process

Example 5: Blend is prepared by dry mixing and film-coating is by non-aqueous coating process

Example 6: Blend is prepared by dry mixing and film-coating is by aqueous coating process

Example 7: Blend is prepared by dry granulation and film-coating is by aqueous coating process

Example 8: Blend is prepared by dry granulation and film-coating is by non-aqueous coating process

Brief manufacturing process: Example 1,2,3 & 4:

i) Sifted all ingredients through #40 mesh

ii) Ibuprofen and microcrystalline cellulose were added to blender and blended for 5 minutes. Granulated the blend using a solution of Povidone K90 in purified water or isopropyl alcohol. The obtained granules were dried in FBD for 10min at 50-55°C and if necessary the dried granules were sized.

iii) Dried granules, codeine phosphate, micro crystalline cellulose, Carmellose calcium
and colloidal silica anhydrous were loaded into blender, and blended for 10min. Added
stearic acid and further blended for 5min.

iv) Blend was compressed into tablets

v) Finally the tablets were coated with solution of Opadry white in purified water or mixture of Isopropyl alcohol and Methylene chloride and then tablets were dried in coating pan.

Examples 5 & 6:

All the ingredients were sifted separately and all the uncoated tablet ingredients were dry mixed for lOmin except stearic acid in a blender. Finally the mixture was lubricated with stearic acid for 5min in a blender and then lubricated blend was compressed into tablets. The tablets were coated with a solution of Opadry white in isopropyl alcohol + methylene chloride (60:40) or purified water.

Examples 7 & 8:

All the ingredients were sifted separately and all the uncoated tablet ingredients were dry mixed for 10min except stearic acid in a blender. The mixture is then slugged using roller compactor or any suitable means, de-slugged and optionally sized. De-slugged blend is lubricated with stearic acid for 5min in a blender and then lubricated blend was compressed into tablets. The tablets were coated with a solution of Opadry white in isopropyl alcohol + methylene chloride (60:40) or purified water.

Packaging: All the film-coated tablets from Examples 1-8 were packaged in PVC/A1

Stability: All the packed tablets from Examples 1-8 were charged into stability chambers at 40°C/ 75% RH

Observations: After period of 6 months at 40°C/ 75% RH the samples withdrawn from stability chambers and observed for physical appearance of tablets, which are as follows:

From the above experiments it has been found that the film-coated tablets prepared by aqueous coating technique are more stable and there is no discoloration during storage.

We Claim:

1. Process for the manufacture of stable film-coated tablets of NSAIDs and Narcotic analgesics, wherein the process comprises coating the uncoated tablets by aqueous coating.

2. Process as claimed in Claim 1, wherein the aqueous coating solution is prepared by dispersing film formers, opacifiers, plasticizers, optionally colorings in water or readymade coating materials in purified water.

3. Process as claimed in Claim 1, where in NSAIDs are selected from Ibuprofen, Aspirin, ketoprofen, Sulindac, Naproxen, Etodolac, fenoprofen, diclofenac, flubiprofen, ketorolac, piroxicam, indomethacin, mefenamic acid, meloxicam, nabumetone, oxaprozin, mecolfenamate, tolmetin, and salsalate and their pharmaceutically acceptable salts, solvates, hydrates thereof.

4. Process as claimed in Claim 1, where in narcotic analgesics are selected from morphine, codeine, meperidine, propoxyphen and their pharmaceutically acceptable salts, solvates, hydrates thereof.

5. Process as claimed in Claim 1 and 3, wherein NSAID is selected from Ibuprofen and its pharmaceutically acceptable salts.

6. Process as claimed in Claim 1 and 4, wherein narcotic analgesic is selected from codeine phosphate and its hydrates.