WO2012059937A1

WO2012059937A1 - Modifies release pharmaceutical compositons for nsaids

Info

Publication number: WO2012059937A1
Application number: PCT/IN2011/000732
Authority: WO
Inventors: Venkat Yadav; Sanjay Boldhane; Shripad Jathar
Original assignee: Abbott Healthcare Private Limited
Priority date: 2010-11-01
Filing date: 2011-10-24
Publication date: 2012-05-10

Abstract

The present invention is directed to a modified release pharmaceutical composition consisting agglomerates comprising one or more NSAIDs and one or more enteric polymers and process for preparing the same.

Description

TITLE :

MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS FORNSAIDs. FIELD OF THE INVENTION:

The present invention relates to a modified release pharmaceutical composition consisting agglomerates comprising one or more NSAIDs and one or more enteric polymers and process for preparing the same.

BACKGROUND OF THE INVENTION:

NSAIDs remain the mainstay of therapy and amongst the most commonly prescribed medications in the world attesting to their efficacy as anti-inflammatory, anti- thrombotic, anti -pyretic, and analgesic agents. During the past 30 years, there has been a substantial increase in the number of clinically available NSAIDs. Their principle mode of action is to block prostaglandin production by binding and inhibiting cyclooxygenase (COX). However, in all patients, NSAIDs should be avoided in the presence of renal or hepatic dysfunction, coagulopathies, gastro- intestinal (GI) disorders, shock, hypotension/ hypovolemia, hypoalbuminemia or pregnancy.

Development of new drug molecule is expensive and time consuming. Improving safety efficacy ratio of "old" drugs has been attempted using different methods such as individualizing drug therapy and therapeutic drug monitoring. Delivering drug at controlled rate, slow delivery, and targeted delivery are other very attractive methods and have been pursued very vigorously. Particularly, a trend in NSAID development has been to improve therapeutic efficacy and reduce the severity of upper GI side effects through altering dosage forms of NSAIDs by modifying release of the formulations to optimize drug delivery. Indeed, enteric coated (EC) and sustained release (SR) formulations of several NSAIDs have resulted in a reduction in endoscopic findings in the stomach and duodenal bulb as these formulations are intended to release NSAIDs in the intestine. Over the last thirty or so years, modified release dosage forms have increasingly become a preferred method of delivering certain drugs to patients, particularly via the oral route. Such forms may for example provide for release of drug(s) at a time other than promptly after administration or over an extended period of time, thus reducing the number of required daily doses, or pulsative. However, modified release formulation technologies and diversity in dosage form design necessitates the development of new procedures or appropriate modification to the existing expertise.

US patent no. 5,711,967 relates to diclofenac preparation with controlled release is in the form of pellets. The active ingredient, applied to inert pellets, is coated with a membrane layer which contains, in addition to 35-65% by weight of a pH independent water-insoluble polymer, 5-20% by weight of at least one water-soluble and/or water-insoluble pore-forming agent and 20-50% by weight of adjuncts. The invention describes that pore-forming agents permit a very uniform release of diclofenac such that administration twice a day is sufficient and a film coating resistant to gastric juice is applied over the membrane layer.

US patent application no. 20090214640 Al relates to a delayed release pharmaceutical oral dosage form and method of making same. The described delayed release dosage form comprises one or more active ingredients within a granulated composition, which further comprises one or more excipients selected from the group of solid aliphatic alcohols, fatty acid esters, mixtures of esters of saturated fatty alcohols and saturated fatty acids, natural waxes, synthetic waxes, hydrogenated castor oil, hydrogenated vegetable oil, gums, and mixtures thereof; and one or more polymers or copolymers exhibiting a pH-dependent solubility. US patent no. 5,202,159 relates a preparation method of sodium diclofenac enteric- coated microcapsules by spray drying technique comprising the steps of (a) dissolving sodium diclofenac in an appropriate amount of distilled water; (b) adding an effective amount of excipients to the above solution to form a suspension; (c) adding methacrylic acid-ethyl acrylate copolymers (Eudragit L 30D) and polyethyleneglycol 6000 (PEG 6000) as the enteric-coating material to form a slurry; d) atomizing the slurry to form spray-dried powder; (e) mixing the spray-dried powder with a mixture of microcrystalline cellulose (neocel) and pregelatinized starch (flo-starch) ; and (f) compressing the powder mixture into a microdispersed enteric tablet. The invention describes that spray drying technique could be easily performed to prepare the enteric-coated microcapsules with aqueous latex polymer dispersion such as Eudragit L 30D as an enteric-coating polymer.

Journal article from Research Journal of Pharmaceutical Dosage Form and Technology (RJPDFT), Volume 02, Issue 01, January-February, 2010 describes a formulation of diclofenac sodium delayed-release disintegrating tablets, which upon oral ingestion rapidly disintegrate into DR pellets without affecting drug release pattern. Various enteric polymers are used to produce DR matrix pellets by high- shear pelletization process and the suitable process variables are also optimized. The optimized DR multiparticulates are compressed with tabletting excipients into multiple unit pellet system (MUPS) tablets. Journal article from International Journal of Pharmaceutics, Volume 62, Issues 2-3, 31 July 1990, Pages 105-111 relates to controlled release indomethacin microspheres with acrylic polymers Eudragit RS and RL, prepared by using two emulsion solvent- diffusion technique and the drug release is described on the basis of two bi- exponential, first-order models.

Although the present platform technology will be useful for plethora of drugs, for the present invention diclofenac was selected as illustration.

Diclofenac chemically known as "2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid" and may be represented by Formula I:

Formula I

Diclofenac is a unique member of the NSAIDs, taken to reduce inflammation and as an analgesic reducing pain in conditions such as arthritis or acute injury. It can also be used to reduce menstrual pain, dysmenorrhea. Diclofenac is available in stomach acid resistant formulations (25 and 50 mg), fast disintegrating oral formulations (25 and 50 mg), slow- and controlled-release forms (75, 100 or 150 mg), suppositories (50 and 100 mg), and injectable forms (50 and 75 mg). Considering the widespread use of diclofenac and the volume of its manufacture, both its manufacture and its use as an analgesic are well known to persons skilled in the art.

The exact mechanism of action for diclofenac is not entirely known, but it is thought that the primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX), and it appears to inhibit DNA synthesis.

In spite of existing prior arts mentioned above there is still need for an invention that is better in controlling symptoms with improved process parameters. The inventors of the present invention have prepared a modified release pharmaceutical composition showing desired release profile of NSAIDs and ease of formulation development and thereby developed orally disintegrating formulations for patients suffering from swallowing difficulties and suitable for pediatric, geriatric and schizophrenia patients.

SUMMARY OF THE INVENTION:

In one aspect the present invention provides modified release orally disintegrating agglomerates comprising one or more NSAIDs and one or more enteric polymers.

In yet another aspect the present invention provides a modified release pharmaceutical composition consisting orally disintegrating enteric agglomerates comprising one or more NSAIDs and one or more enteric polymers.

In yet another aspect the present invention provides a process of preparing a modified release pharmaceutical composition consisting orally disintegrating enteric agglomerates comprising one or more NSAIDs and one or more enteric polymers wherein the process uses emulsion solvent diffusion technique

DETAILED DESCRIPTION OF THE INVENTION:

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set forth below. The term "modified release" pharmaceutical composition will be well understood by the skilled person to include any composition/formulation in which the onset and/or rate of release of drug is altered by galenic manipulations.

The term "delayed release" as used herein means the release of active ingredient is delayed for 4-6 hours (lag time) and where drug release should not be more than 10 % of label claim.

The term "enteric polymers" as used herein refers to polymers which have pH dependent solubility.

The examples of NSAIDs includes but are not limited to celecoxib, rofecoxib, meloxicam, piroxicam, valdecoxib, parecoxib, etoricoxib, aceclofenac, aspirin, acetaminophen, ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, nabumetone, or diclofenac and pharmaceutically acceptable salts thereof.

The examples of enteric polymers includes but are not limited to cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, alkali-soluble acrylic copolymer, polyvinyl acetate phthalate or mixtures thereof.

The formulation will, in general comprise of one or more excipients. Examples of pharmaceutically acceptable excipients include, but are not limited to, diluents, disintegrants, lubricant, glidant, binders, fillers, surfactant, solubilizers, wetting agents, chelating agents, stabilizers, alkalizing agents or amino acids. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trade marks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations there of and other materials known to one of ordinary skill in the art.

Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used. Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al, Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.

Glidants include, but are not limited to, silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art. The pharmaceutical composition according to the present invention include but are not limited to tablets (single layered tablets, multilayered tablets, mini tablets, orally disintegrating tablets, chewable tablets, dispersible tablets, caplets, granules, capsules, microcapsules, granules for suspension, conventional suspension. The invention described herein is preferably orally disintegrating agglomerates based on delayed release dosage form. The technology comprises enteric agglomerates of NSAIDs prepared by using emulsion solvent diffusion technique providing delayed release orally disintegrating dosage form.

The technology provides two approaches i) initial disintegration within few minutes in oral cavity ii) followed by dissolution of active ingredient in alkaline medium. The said technology relates to provide enteric agglomerates comprising active ingredient prepared by emulsion solvent diffusion technique. The prepared agglomerates showed better process parameters like decrease in density and significant improvement in flowability due to lower values for compressibility index, hausnar ratio and higher values for flow rate. The improvement of dissolution in alkaline medium may be due to i) disintegration of dosage form in oral cavity and thus bypass the disintegration step in intestinal alkaline medium and/or ii) there may be formation of co-crystal agglomerates as the enteric polymer forms noncovalent bond with the acidic group of active ingredient. The present enteric multiparticulate system is less dependant on gastric emptying as the individual subunit particles pass rapidly through the gastrointestinal tract and able to leave the stomach continuously, even if the pylorus is closed, resulting in less inter and intra subject variability in gastrointestinal transit time. Also as the orally disintegrating pharmaceutical composition disintegrates in the oral cavity, it is available in suspension form in intestine for dissolution thus bypasses the disintegration step.

The pharmaceutical dosage form of the present invention may comprise tablet, capsule or sachet, preferably tablet, more preferably directly compressible tablet in a single dosage form or multiple dosage forms such as when different components are maintained separately and are admixed prior to administration or are sequentially administered or simultaneously co-administered or when two or more of the same dosage form are administered to achieve the required therapeutic dose of active ingredient selected from the class of NSAIDs. The various embodiments of the present invention can be assembled in several different ways.

In one embodiment the present invention provides a modified release pharmaceutical composition consisting of agglomerates comprising: a) one or more NSAIDs; b) one or more enteric polymers; c) one or more pharmaceutically acceptable excipients.

In yet another embodiment the present invention provides a delayed release pharmaceutical composition consisting of agglomerates comprising: a) one or more NSAIDs; b) one or more enteric polymers; c) one or more pharmaceutically acceptable excipients.

In yet another embodiment the present invention provides a modified release orally disintegrating tablet consisting of agglomerates comprising: a) one or more NSAIDs; b) one or more enteric polymers; c) one or more pharmaceutically acceptable excipients. In yet another embodiment the present invention provides a process of preparing modified release orally disintegrating tablet consisting of agglomerates comprising: a) one or more NSAIDs; b) one or more enteric polymers; c) one or more pharmaceutically acceptable excipients wherein the agglomerates are prepared using emulsion solvent diffusion technique.

In yet another embodiment the present invention provides a modified release orally disintegrating tablet consisting of agglomerates comprising: a) diclofenac or pharmaceutically acceptable salts thereof; b) cellulose ether phthalate; c) one or more pharmaceutically acceptable excipients.

In yet another embodiment the present invention provides a process of preparing modified release orally disintegrating tablet consisting of agglomerates comprising: a) diclofenac or pharmaceutically acceptable salts thereof; b) cellulose ether phthalate; c) one or more pharmaceutically acceptable excipients. wherein the agglomerates are prepared using emulsion solvent diffusion technique.

In yet another embodiment the present invention provides a modified release pharmaceutical composition in the form of agglomerates comprising: a) one or more NSAIDs; b) one or more enteric polymers; c) one or more pharmaceutically acceptable excipients.

In a preferred embodiment a modified release orally disintegrating tablet consisting of agglomerates according to present invention comprises of one or more enteric polymers which are present from about 0.1% to about 20% w/w of the composition. In a preferred embodiment a modified release orally disintegrating tablet consisting of agglomerates according to present invention has preferable ratio of NSAID to enteric polymer as 10:1.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the present invention. The examples should not be read as limiting the scope of the present invention.

Example 1

The present modified release pharmaceutical composition can be prepared as described below. Table 1

Procedure:

1. Dissolved the weighed quantity of hypromellose phthalate in ethanol- acetone-dichloromethane combination of organic solvent by sonication.

2. Dispersed the weighed quantity of diclofenac in above prepared

hypromellose phthalate solution by sonication.

3. Poured the prepared dispersion slowly in distilled water with stirring for 15 minutes at room temperature.

4. After 15 minutes the solid agglomerates were filtered by and dried in hot air oven at 50 - 60 °C.

5. Sifted the dried granules through sieve no # 25-30 to form uniform granules.

6. Stored the granules for formulation and preparation of ODT tablet. Example 2

The pharmaceutical dosage form as prepared in example 1 was evaluated for flowability and density parameters and the results are shown in table 2. Table 2

* Vibration required for flow

Example 3

The pharmaceutical composition as prepared in example- 1 was converted into pharmaceutical dosage form like tablet by direct compression as shown in table 3. Table 3

Direct compression technique:

Example 4

The pharmaceutical dosage form (test composition) as prepared in example was compared with commercial tablets Voveran® for dissolution as shown and the results obtained are shown in table 5.

Table 4

Dissolution conditions:

Table 5

Dissolution study of the present test composition and marketed delayed release diclofenac tablet Voveran® in 0.1N HCI and phosphate buffer pH 6.8

Example 5

The present modified release pharmaceutical composition can be prepared as described below.

Table 6

1. Dissolved the weighed quantity of hypromellose acetate succinate in ethanol- acetone-dichloromethane combination of organic solvent by sonication.

2. Dispersed the weighed quantity of aceclofenac in above prepared

hypromellose acetate succinate solution by sonication.

4. After 15 minutes the solid agglomerates were filtered and dried in hot air oven at 50 - 55 °C.

5. Sifted the dried granules through sieve no # 25-30 to form uniform granules.

6. Stored the granules for formulation and preparation of ODT tablet. Example 6

The pharmaceutical dosage form as prepared in example 5 was evaluated for flowability and density parameters and the results are shown in table 7. Table 7

Example 7

The pharmaceutical composition as prepared in example-5 was converted into pharmaceutical dosage form like tablet by direct compression as shown in table 8.

Table 8

Direct compression technique:

Example 8

Table 9

2. Dispersed the weighed quantity of naproxen in above prepared hypromellose phthalate solution by sonication.

4. After 15 minutes the solid agglomerates were filtered and dried in hot air oven at 55-60°C.

5. Sifted the dried granules through sieve no # 25-30 to form uniform granules.

6. Stored the granules for formulation and preparation of ODT tablet. Example 9

The pharmaceutical dosage form as prepared in example 8 was evaluated for flowability and density parameters and the results are shown in table 10. Table 10

Example 10

The pharmaceutical composition as prepared in example-8 was converted into pharmaceutical dosage form like tablet by direct compression as shown in table 11. Table 11

Direct compression technique:

Example 11

Table 12

Procedure:

2. Dispersed the weighed quantity of ibuprofen in above prepared hypromellose phthalate solution by sonication.

4. After 15 minutes the solid agglomerates were filtered and dried in hot air oven at 45-50°C.

5. Sifted the dried granules through sieve no # 25-30 to form uniform granules. 6. Stored the granules for formulation and preparation of ODT tablet. Example 12

The pharmaceutical dosage form as prepared in example 11 was evaluated for flowability and density parameters and the results are shown in table 13. Table 13

Example 13

The pharmaceutical composition as prepared in example- 11 was converted into pharmaceutical dosage form like tablet by direct compression as shown in table 14.

Table 14

Direct compression technique:

Claims

1. A modified release pharmaceutical composition consisting of agglomerates comprising : a) one or more NSADDs; b) one or more enteric polymers; c) one or more pharmaceutically acceptable excipients.

2. A composition according to claim 1 wherein the agglomerates are prepared using emulsion solvent diffusion technique.

3. A composition according to claim 1 wherein NSAID can be selected from group consisting of celecoxib, rofecoxib, meloxicam, piroxicam, valdecoxib, parecoxib, etoricoxib, aceclofenac, aspirin, acetaminophen, ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, nabumetone, or diclofenac and pharmaceutically acceptable salts thereof.

4. A composition according to claim 1 wherein enteric polymer can be selected from group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, alkali-soluble acrylic copolymer, polyvinyl acetate phthalate or mixtures thereof.

5. A modified release orally disintegrating tablet consisting of agglomerates comprising: a) one or more NSAIDs; b) one or more enteric polymers; c) one or more pharmaceutically acceptable excipients.

6. An orally disintegrating tablet according to claim 5 wherein the agglomerates are prepared using emulsion solvent diffusion technique.

7. An orally disintegrating tablet according to claim 5 wherein NSAID can be selected from group consisting of celecoxib, rofecoxib, meloxicam, piroxicam, valdecoxib, parecoxib, etoricoxib, aceclofenac, aspirin, acetaminophen, ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac, lornoxicam, nabumetone, or diclofenac and pharmaceutically acceptable salts thereof.

8. An orally disintegrating tablet according to claim 5 wherein enteric polymer can be selected from group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, alkali- soluble acrylic copolymer, polyvinyl acetate phthalate or mixtures thereof.

9. A modified release orally disintegrating tablet consisting of agglomerates comprising: a) diclofenac or pharmaceutically acceptable salts thereof; b) hydroxypropyl methylcellulose phthalate c) one or more pharmaceutically acceptable excipients.

10. An orally disintegrating tablet according to claim 9 wherein the agglomerates are prepared using emulsion solvent diffusion technique.

11. A modified release orally disintegrating tablet consisting of agglomerates comprising: a) ibuprofen or pharmaceutically acceptable salts thereof; b) hydroxypropyl methylcellulose phthalate c) one or more pharmaceutically acceptable excipients.

12. An orally disintegrating tablet according to claim 11 wherein the agglomerates are prepared using emulsion solvent diffusion technique.