WO2006103551A1

WO2006103551A1 - Controlled release formulations of oxycodone

Info

Publication number: WO2006103551A1
Application number: PCT/IB2006/000753
Authority: WO
Inventors: Anurag Sood; Rajan Kumar Verma; Rajeev Singh Raghuvanshi; Ashok Kumar Rampal
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2005-03-31
Filing date: 2006-03-31
Publication date: 2006-10-05

Abstract

The present invention relates to controlled release formulations of oxycodone with one or more hydrophilic controlled release polymers, and processes for their preparation.

Description

CONTROLLED RELEASE FORMULATIONS OF OXYCODONE

Technical Field of the Invention

The present invention relates to controlled release formulations of oxycodone with one or more hydrophilic controlled release polymers, and processes for their preparation. Background of the Invention

It is well known in the pharmaceutical art to prepare formulations that provide for a controlled release of pharmacologically active substances after oral administration to humans and animals. The controlled release of a medicament in the gastrointestinal tract maintains the desired concentration of the medicament in the blood stream for a longer duration than would occur if using a conventional rapid release dosage form. It is the intent of all controlled release formulations to provide a longer period of therapeutic response after the administration of the drug when compared to that experienced after the administration of the rapid release dosage forms. This longer period of response provides for many therapeutic benefits that are not achieved with corresponding short acting, conventional immediate release formulations.

Controlled release formulations known in the art include such formulations as enteric-coated pellets, matrix tablets, granules, capsules, and/or pharmaceutical formulations wherein the active ingredients are dispersed in a medium totally insoluble in physiologic fluids. Additionally, controlled release formulations may include those where the release of the active medicament is brought about by breakdown of the formulation due to mechanical means.

Surveys of daily dosages of opioid analgesics required to control pain suggest that an approximately eight-fold range in daily dosages is required to control pain in approximately 90% of patients. This wide range in the appropriate dosage makes the titration process time and resource consuming, as well as leaving the patient without acceptable pain control for an unacceptably long duration. An opioid analgesic treatment, which acceptably controls pain over a substantially narrower daily dosage range, would improve the efficiency and quality of pain management.

Oxycodone is an opioid analgesic that has been widely used in the treatment of various types of pain. Repeated dose studies with controlled release oxycodone formulations administered every 12 hours, in comparison with immediate release oral oxycodone administered every 6 hours at the same total daily dose, resulted in comparable absorption, and maximum and minimum concentrations.

It is known in the art that controlled release compositions of opioid analgesics, such as morphine, hydromorphone or salts thereof may be prepared with a suitable matrix. U.S. 4,990,341 discloses hydromorphone compositions wherein the dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method at 100 rpm in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37⁰C, is between 12.5% and 42.5% (by wt) hydromorphone released after 1 hour, between 25% and 55% (by wt) released after 2 hours, between 45% and 75% (by wt) released after 4 hours and between 55% and 85% (by wt) released after 6 hours.

U.S. 4,235,870 discloses slow release pharmaceutical compositions prepared with a sustained release matrix comprising a combination of a higher aliphatic alcohol and a hydrated hydroxyalkyl cellulose in ratio of from 2:1 to 4: 1 parts by weight and comprising from 20 to 40 percent by weight of the composition. Furthermore, the patent teaches that a critical ratio, in terms of parts by weight, of higher aliphatic alcohol to hydrated hydroxy-alkyl cellulose, results in a new synergistic action, which potentiates the rate of drug release for the aliphatic alcohol in the aforementioned combination.

U.S. 5,508,042 discloses an oral solid controlled release dosage formulation of oxycodone containing a combination of hydrophilic polymer, an acrylic acid polymer and an aliphatic alcohol. This patent further teaches that such a combination of polymers and aliphatic alcohol as a controlled release composition results in the pH independent release of oxycodone evenly throughout the gastrointestinal tract and thus avoids the dose dumping upon oral administration. U.S. 4,861,598 discloses the controlled release bases containing the combination of the aliphatic alcohol and acrylic resin for the extended release of therapeutic agents. This patent teaches that the optimum control of drug release and a delay in retardation of generally 5-12 hours can be achieved by utilizing the matrix base of the invention in a range of 20-40% by weight of the total weight of the selected dosage unit. The patent further discloses that when using the acrylic resins in combination with the higher aliphatic alcohol there was unexpectedly an increase in the control of the drug release properties for the flow and controlled release of medicaments. This increase in action is particularly apparent when using a highly water-soluble therapeutic agent.

The prior art teaches the use of combinations of hydrophilic polymers along with aliphatic alcohols or acrylic acid polymers to achieve the desired release characteristics of the incorporated medicament in the gastrointestinal tract. Further, the combinations of these hydrophilic polymers, along with aliphatic alcohols or acrylic acid polymers, result in the controlled release of medicaments with a pH independent release profile. Surprisingly, we have found that the hydrophilic polymer alone can be used as the controlled release formulation component that gives the desired controlled release with pH independent release profile for freely water-soluble drugs, such as oxycodone or oxycodone hydrochloride. These formulations further show pH-independent and agitation-independent release of oxycodone. The properties are advantageous for oral controlled release formulations that experience variable hydrodynamic stress as it moves through the length of the gastrointestinal tract. Unlike prior art formulations, the formulations of the present invention are cost effective and easy to manufacture on commercial scale without requiring complex processing steps.

Summary of the Invention

In one general aspect there is provided a controlled release oxycodone formulation consisting essentially of a therapeutically effective amount of oxycodone or salt thereof and one or more hydrophilic controlled release polymers. This formulation may optionally include one or more pharmaceutically acceptable excipients.

Embodiments of the present invention may include one or more of the following features. For example, the formulation may have a pH-independent in vitro dissolution profile. The formulation may also have an agitation-independent in vitro dissolution profile.

The one or more hydrophilic controlled release polymers may include one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone-based polymers and mixtures thereof. The cellulose derivatives may include one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. The gums may include one or more of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate and mixtures thereof. The vinyl alcohol or vinylpyrrolidone-based polymers may include one or more of polyvinyl alcohol, polyvinylpyrrolidone and mixtures thereof.

For example, the one or more hydrophilic controlled release polymers may be hydroxypropyl methylcellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose, or hydroxypropyl methylcellulose and sodium carboxymethyl cellulose. The one or more hydrophilic controlled release polymers may be present at a concentration of from about 10% to about 90% based on the weight of the formulation.

In another general aspect there is provided a controlled release formulation of oxycodone consisting essentially of a therapeutically effective amount of oxycodone or salt thereof, one or more hydrophilic controlled release polymers, and optionally one or more pharmaceutically acceptable excipients. The formulation exhibits a dissolution profile where between about 15% to about 45% of the oxycodone is released after about 1 hour, between about 30% to about 60% of the oxycodone is released after about 2 hours, between about 55% to about 90% of the oxycodone is released after about 4 hours, between about 70% to about 95% of the oxycodone is released after about 6 hours and between about 85% to about 100% of the oxycodone is released after about 8 hours.

Embodiments of the formulation may include one or more of the following features. For example, the formulation may have a pH-independent in vitro dissolution profile or an agitation-independent in vitro dissolution profile. The one or more hydrophilic controlled release polymers may include one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone-based polymers and mixtures thereof. The cellulose derivatives may include one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. The gums may include one or more of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate and mixtures thereof. The vinyl alcohol or vinylpyrrolidone-based polymers may include one or more of polyvinyl alcohol, polyvinylpyrrolidone and mixtures thereof.

In yet another general aspect there is provided a method of treating pain in mammals in need thereof. The method includes administering a controlled release formulation of oxycodone consisting essentially of a therapeutically effective amount of oxycodone or salt thereof, one or more hydrophilic controlled release polymers, and optionally one or more pharmaceutically acceptable excipients. The formulation exhibits a dissolution profile where between about 15% to about 45% of the oxycodone is released after about 1 hour, between about 30% to about 60% of the oxycodone is released after about 2 hours, between about 55% to about 90% of the oxycodone is released after about 4 hours, between about 70% to about 95% of the oxycodone is released after about 6 hours and between about 85% to about 100% of the oxycodone is released after about 8 hours.

Embodiments of the present method may include one or more of the following features. For example, the formulation may have a pH-independent in vitro dissolution profile or an agitation-independent in vitro dissolution profile.

The one or more hydrophilic controlled release polymers may include one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone-based polymers and mixtures thereof. The cellulose derivatives may include one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. The gums may include one or more of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate and mixtures thereof. The vinyl alcohol or vinylpyrrolidone based polymers may include one or more of polyvinyl alcohol, polyvinylpyrrolidone and mixtures thereof.

Detailed Description of the Invention

The controlled release formulations of oxycodone consist essentially of oxycodone or a salt thereof, one or more hydrophilic controlled release polymers and optionally one or more pharmaceutically acceptable excipients. When administered orally the formulations release oxycodone or salt thereof in a controlled release manner over a prolonged period of time.

According to one embodiment, the formulations prepared show a pH-independent dissolution profile. These formulations may show an in vitro dissolution profile of oxycodone or salt thereof wherein between abut 15% and about 45% is released after about 1 hour, between about 30% and about 60% is released after about 2 hours, between about 55% and about 90% is released after about 4 hours, between about 70% and about 95% is released after about 6 hours, and between about 85% and about 100% is released after about 8 hours. The dissolution is measured using the USP I Method, at 100 rpm, in 900 ml aqueous buffer (pH 1.2 to 6.8), at 37 ± 0.5⁰C. The formulation releases oxycodone at a pH-independent rate, thereby avoiding dose dumping upon oral administration. Surprisingly, this dissolution profile may be achieved with the use of one or more hydrophilic controlled release polymers alone. The term "pH-independent dissolution profile" as used herein means that the difference at any point in time is the same for any amount of oxycodone or salt thereof released at between pH 1.2 and pH 6.8 (as measured in vitro using USP I Method, at 100 rpm, in 900 ml aqueous buffer, at 37 ± 0.5⁰C) is not more than about 10%. However, a pH-independent release profile may also be obtained using aqueous buffers with different pH, such as 1.2, 4.5 and 6.8.

According to another embodiment, the formulations prepared show a pH independent and an agitation independent dissolution profile. This provides improved resistance against hydrodynamic impact over the length of gastrointestinal tract. These formulations may show an in vitro dissolution profile of oxycodone or salt thereof wherein the amount of oxycodone released is between about 15% and about 45% after about 1 hour, between about 30% and about 60% after about 2 hours, between about 55% and about 90% after about 4 hours, between about 70% and about 95% after about 6 hours, and between about 85% and about 100% after about 8 hours. This dissolution profile is measured using the USP I Method, at 100 rpm, in 900 ml aqueous buffer (pH 1.2 to 6.8), at 37 ± 0.5⁰C. The formulation releases oxycodone at a pH-independent rate and an agitation-independent rate, thereby avoiding dose dumping upon oral administration. Surprisingly, this dissolution profile may be achieved with the use of one or more rate controlling hydrophilic polymers alone.

The term "agitation-independent dissolution profile" as used herein means that the difference at any point in time between the amount of oxycodone or salt thereof released at 25 rpm and 100 rpm (as measured in vitro using USP I Method, in 900 ml aqueous buffer, at 37 ± 0.5⁰C) is not more than about 10%. However, agitation-independent release may also be obtained using different rpms, such as 25, 50, 75 and 100.

The controlled release formulation may preferably contain oxycodone in the range of between about 1 mg to about 500 mg, preferably between about 10 mg to about 160 mg. The formulation may also include oxycodone salts. For example, the salt may be oxycodone hydrochloride.

The "hydrophilic controlled release polymer" may include one or more of cellulose derivatives, such as one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose and sodium carboxymethyl cellulose; gums, such as one or more of xanthan gum, karaya gum, and locust bean gum, alginic acid, and sodium alginate; and vinyl alcohol or vinylpyrrolidone based polymers, such as one or more of polyvinyl alcohol and polyvinylpyrrolidone. The hydrophilic controlled release polymers may be present at concentration of from about 10% to about 90% based on the weight of total tablet. For example, the hydrophilic controlled release polymers may be present at a concentration of from about 20% to about 80% or from about 40% to about 60%. The hydrophilic controlled release polymer may be hydroxypropyl methyl cellulose.

The formulations may also include one or more additional release retarding polymers. However, hydrophilic polymers alone may be used to obtain the controlled release formulations with desirable characteristics of the invention. Thus the controlled release formulation may consist essentially of oxycodone or salts thereof, and one or more hydrophilic polymers.

The controlled release formulation may also include one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients may include one or more of diluents, binders, lubricants, glidants and mixtures thereof. Suitable diluents may include one or more of microcrystalline cellulose, lactose, dicalcium phosphate and starch. Suitable binders may include one or more of starch, polyvinylpyrrolidone, natural or synthetic gum and cellulosic polymers. Suitable lubricants and glidants may include one or more of talc, colloidal silicon dioxide and magnesium stearate.

The controlled release formulation of oxycodone may be in the form of various dosage forms, such as tablets, beads, pellets or capsules. The tablet may be a coated tablet or minitablets. For example, the formulations may in the form of matrix tablets with or without a coating. These dosage forms provide pH-independent or pH- and agitation- independent release of oxycodone or salts thereof. The formulations of the present invention show pH-independent or pH- and agitation-independent release of oxycodone or salts thereof, regardless of the process of manufacture. Thus the tablet may be prepared by one or more of wet granulation, dry granulation or direct compression processes. The following non-limiting examples further illustrate the controlled release formulations of oxycodone or salt thereof, process of making and using such formulations.

Examples 1-2

Process of preparation:

1. Oxycodone hydrochloride, hydroxypropyl methylcellulose and lactose were sifted through an ASTM #30 sieve.

2. Polyvinylpyrrolidone (PVP-K30) was dissolved in isopropyl alcohol to obtain a 10% w/w solution.

3. The materials of step 1 were mixed together in a rapid mixer granulator for 15 minutes followed by granulation with the solution of step 2 to obtain granules.

4. The granules of step 3 were dried at about 6O⁰C to about 70⁰C to remove the isopropyl alcohol and get water by KF value of NMT 4%w/w.

5. The dried granules of step 4 were blended with colloidal silicon dioxide (previously sifted through an ASTM #30 sieve) for 10 minutes in a V-blender to obtain a blend. 6. The blend of step 5 was lubricated with magnesium stearate (previously sifted through an ASTM #40) for 5 minutes in a V-blender to obtain a final blend.

7. The final blend of step 6 was compressed to tablets.

8. The tablets of step 7 were coated with Opadry OY-S-58910 aqueous dispersion (12% w/w solids concentration) to a weight gain of about 2% to about 3% w/w.

Examples 3-9

Process of preparation: 1. Oxycodone hydrochloride, hydroxypropyl methylcellulose and lactose were sifted through an ASTM #30 sieve and mixed together to obtain a dry powder mix. 2. Colloidal silicon dioxide was sifted through an ASTM #30 sieve and blended with the dry powder mix of step 1 to obtain a blend. 3. Magnesium stearate was sifted through an ASTM #40 sieve and mixed with the blend of step 2 to obtain a final blend.

4. The tablets were compressed with the final blend of step 3.

5. The tablets of step 4 were coated with opadry white OY-S-58910 to a weight gain of about 2.0% to about 3.0% w/w.

Examples 10-11

Process of preparation: 1. Oxycodone hydrochloride, hydroxypropyl methylcellulose, microcrystalline cellulose and lactose were sifted through an ASTM #30 sieve and mixed together to obtain a dry powder mix. 2. The dry powder mix of step 1 was compacted, followed by milling, to obtain the granules. 3. Colloidal silicon dioxide was sifted through an ASTM #30 sieve and blended with the granules of step 2 to obtain a blend.

4. Magnesium stearate was sifted through an ASTM #40 sieve and mixed with the blend of step 3 to obtain a final blend.

5. The tablets were compressed with the final blend of step 4. Examples 12-13

* Dry granulated.

Process of preparation:

1. Hydroxypropyl methylcellulose (-granules) was dry granulated by a compaction process to obtain the granules sized through an ASTM #16 or #20 sieve and retained on an ASTM #60 sieve.

2. Oxycodone hydrochloride, hydroxypropyl methylcellulose and lactose were sifted through an ASTM #30 sieve.

3. The materials of step 1 and 2 were mixed together to obtain a blend.

4. Colloidal silicon dioxide was sifted through an ASTM #30 sieve and blended with the blend of step 3.

5. Magnesium stearate was sifted through an ASTM #40 sieve and mixed with the blend of step 4 to obtain a final blend.

6. The tablets were compressed with the final blend of step 5.

Examples 14-15

* Percent by weight of the tablet Process of preparation:

3. The materials of step 1 were mixed together in rapid mixer granulator for 15 minutes followed by granulation with solution of step 2 to obtain granules.

4. The granules of step 3 were dried at about 6O⁰C to about 7O⁰C to remove isopropyl alcohol and get water by KF value of NMT 4 %w/w.

5. The dried granules of step 4 were blended with colloidal silicon dioxide (previously sifted through an ASTM #30 sieve) for 10 minutes in a V-blender to obtain a blend.

6. The blend of step 5 was lubricated with magnesium stearate (previously sifted through an ASTM #40 sieve) for 5 minutes in a V-blender to obtain a final blend.

7. The final blend of step 6 was compressed into tablets.

8. The tablets of step 7 were coated with Opadry Pink 02B94188 (Example 15) or Opadry Yellow 02B52157 (Example 14) aqueous dispersion to a weight gain of about 2.5% to about 3% w/w. The in vitro release profiles of oxycodone in the various examples set forth above, as measured by the method described herein, are listed below. It should be understood that any suitable method may be used to obtain the in vitro release profile of oxycodone.

Example 1

Example 3

Example 4

Example 14-15

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

We Claim: 1. A controlled release oxycodone formulation consisting essentially of a therapeutically effective amount of oxycodone or salt thereof, one or more hydrophilic controlled release polymers, and optionally one or more pharmaceutically acceptable excipients. 2. The controlled release formulation according to claim 1 , wherein the formulation has a pH-independent in vitro dissolution profile. 3. The controlled release formulation according to claim 1, wherein the formulation has an agitation-independent in vitro dissolution profile. 4. The controlled release formulation according to claim 1 , wherein the one or more hydrophilic controlled release polymers comprises one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone based polymers and mixtures thereof. 5. The controlled release formulation according to claim 4, wherein the cellulose derivatives comprise one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. 6. The controlled release formulation according to claim 4, wherein the gums comprise one or more of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate and mixtures thereof. 7. The controlled release formulation according to claim 4, wherein the vinyl alcohol or vinylpyrrolidone based polymers comprises one or more of polyvinyl alcohol, polyvinylpyrrolidone and mixtures thereof. 8. The controlled release formulation according to claim 5, wherein the one or more hydrophilic controlled release polymers comprise hydroxypropyl methylcellulose 9. The controlled release formulation according to claim 5, wherein the hydrophilic controlled release polymers comprise hydroxypropyl methylcellulose and hydroxypropyl cellulose. 10. The controlled release formulation according to claim 5, wherein the hydrophilic controlled release polymers comprise hydroxypropyl methylcellulose and sodium carboxymethyl cellulose. 11. The controlled release formulation according to claim 1 , wherein the one or more hydrophilic controlled release polymers comprises a concentration of from about 10% to about 90% based on the weight of the formulation. 12. A controlled release formulation of oxycodone consisting essentially of a therapeutically effective amount of oxycodone or salt thereof, one or more hydrophilic controlled release polymers, and optionally one or more pharmaceutically acceptable excipients, wherein the formulation exhibits a dissolution profile where between about 15% to about 45% of the oxycodone is released after about 1 hour, between about 30% to about 60% of the oxycodone is released after about 2 hours, between about 55% to about 90% of the oxycodone is released after about 4 hours, between about 70% to about 95% of the oxycodone is released after about 6 hours, and between about 85% to about 100% of the oxycodone is released after about 8 hours. 13. The controlled release formulation according to claim 12, wherein the formulation has a pH-independent in vitro dissolution profile. 14. The controlled release formulation according to claim 12, wherein the formulation has an agitation-independent in vitro dissolution profile. 15. The controlled release formulation according to claim 12, wherein the one or more hydrophilic controlled release polymers comprises one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone-based polymers and mixtures thereof. 16. The controlled release formulation according to claim 15, wherein the cellulose derivatives comprise one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. 17. The controlled release formulation according to claim 15, wherein the gums comprise one or more of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate and mixtures thereof. 18. The controlled release formulation according to claim 15, wherein the vinyl alcohol or vinylpyrrolidone based-polymers comprises one or more of polyvinyl alcohol, polyvinylpyrrolidone and mixtures thereof. 19. A method of treating pain in a mammal in need thereof, the method comprising administering a controlled release formulation of oxycodone consisting essentially of a therapeutically effective amount of oxycodone or salt thereof, one or more hydrophilic controlled release polymers, and optionally one or more pharmaceutically acceptable excipients, wherein the formulation exhibits a dissolution profile where between about 15% to about 45% of the oxycodone is released after about 1 hour, between about 30% to about 60% of the oxycodone is released after about 2 hours, between about 55% to about 90% of the oxycodone is released after about 4 hours, between about 70% to about 95% of the oxycodone is released after about 6 hours, and between about 85% to about 100% of the oxycodone is released after about 8 hours. 20. The method according to claim 19, wherein the formulation has a pH independent in vitro dissolution profile. 21. The method according to claim 19, wherein the formulation has an agitation- independent in vitro dissolution profile. 22. The method according to claim 19, wherein the one or more hydrophilic controlled release polymers comprises one or more of cellulose derivatives, gums, vinyl alcohol or vinylpyrrolidone-based polymers and mixtures thereof.