Patent Grant
9561242
The present invention relates to a once daily pharmaceutical composition comprising doxycycline, a controlled-release polymer, and one or more pharmaceutically acceptable excipients. The invention further provides a method of treatment of rosacea by administering such pharmaceutical composition. A process of preparing such pharmaceutical composition is also provided.
Food effect refers to food-drug interactions which lead to either a decrease or an increase of the extent of drug absorption. The commercially available capsules of doxycycline (Oracea® 40 mg capsules) for the treatment of inflammatory lesions (papules and pustules) of rosacea is a combination of immediate-release (30 mg) and delayed-release (10 mg) components. As per the prescribing information, Oracea has significant food effect and thus is recommended to be taken on an empty stomach, preferably at least one hour prior to or two hours after meals. Its Cmax and AUC0-t decrease by 45% and 22%, respectively, when taken along with food.
Therefore, there exists a need for a pharmaceutical composition of doxycycline which is capable of reducing the food effect of doxycycline. The present inventors have developed a pharmaceutical composition of doxycycline with reduced food effect which would enable the patient to take the drug without regard to meals, thereby improving patient convenience and compliance.
The present invention relates to a once daily pharmaceutical composition comprising doxycycline, a controlled-release polymer and one or more pharmaceutically acceptable excipients. The invention further provides a method of treatment of rosacea by administering such pharmaceutical composition. A process of preparing such pharmaceutical composition is also provided. It is possible to reduce the dose if food effect is minimized, as the same therapeutic levels may be achieved with a lesser amount of doxycycline.
A first aspect of the invention provides a once daily pharmaceutical composition comprising doxycycline, a controlled-release polymer, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition contains up to 40 mg of doxycycline.
According to one embodiment of the above aspect, the pharmaceutical composition contains from 24 mg to 40 mg of doxycycline.
According to another embodiment of the above aspect, the pharmaceutical composition contains 40 mg of doxycycline.
According to another embodiment of the above aspect, the pharmaceutical composition contains 36 mg of doxycycline.
According to another embodiment of the above aspect, the pharmaceutical composition contains 32 mg of doxycycline.
According to another embodiment of the above aspect, the pharmaceutical composition contains 30 mg of doxycycline.
According to yet another embodiment of the above aspect, the pharmaceutical composition is a capsule or a tablet.
A second aspect of the invention provides a once daily pharmaceutical composition comprising doxycycline and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition exhibits a reduced food effect such that the food effect on Cmax is less than 40% and/or AUC0-t is less than 20% as compared to when the pharmaceutical composition is administered in a fasted state.
According to one embodiment of the above aspect, the food effect on Cmax is less than 20% as compared to when the pharmaceutical composition is administered in a fasted state.
According to another embodiment of the above aspect, the once daily pharmaceutical composition comprises (i) 50% to 99% of doxycycline and one or more pharmaceutically acceptable excipients as an immediate-release portion; and (ii) 1% to 50% of doxycycline, a controlled-release polymer, and one or more pharmaceutically acceptable excipients as a controlled-release portion.
According to the above embodiment, the immediate-release portion contains 85% of doxycycline and the controlled-release portion contains 15% of doxycycline.
According to the above embodiment, the immediate-release portion contains 34 mg of doxycycline and the controlled-release portion contains 6 mg of doxycycline.
According to the above embodiment, the immediate-release portion contains 75% of doxycycline and the controlled-release portion contains 25% of doxycycline.
According to the above embodiment, the immediate-release portion contains 30 mg of doxycycline and the controlled-release portion contains 10 mg of doxycycline.
According to the above embodiment, the immediate-release portion contains 66% of doxycycline and the controlled-release portion contains 34% of doxycycline.
According to the above embodiment, the immediate-release portion contains 26.4 mg of doxycycline and the controlled-release portion contains 13.6 mg of doxycycline.
According to the above embodiment, the immediate-release portion contains 65% of doxycycline and the controlled-release portion contains 35% of doxycycline.
According to the above embodiment, the immediate-release portion contains 26 mg of doxycycline and the controlled-release portion contains 14 mg of doxycycline.
According to the above embodiment, the immediate-release portion contains 60% of doxycycline and the controlled-release portion contains 40% of doxycycline.
According to the above embodiment, the immediate-release portion contains 24 mg of doxycycline and the controlled-release portion contains 16 mg of doxycycline.
According to another embodiment of the above aspect, the pharmaceutical composition comprises only the immediate-release portion.
According to another embodiment of the above aspect, the pharmaceutical composition comprises only the controlled-release portion.
A third aspect of the present invention provides a process for the preparation of a once daily pharmaceutical composition comprising doxycycline and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition exhibits a reduced food effect, and wherein the process comprises:
According to one embodiment of the above aspect, the pharmaceutical composition is a capsule or a tablet.
According to another embodiment of the above aspect, the pharmaceutical composition comprises only the immediate-release portion.
According to another embodiment of the above aspect, the pharmaceutical composition comprises only the controlled-release portion.
A fourth aspect of the present invention provides a method of treating rosacea by administering to a person in need thereof a once daily pharmaceutical composition comprising doxycycline and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition exhibits a reduced food effect such that the food effect on Cmax is less than 40% and/or AUC0-t is less than 20% as compared to when the pharmaceutical composition is administered in a fasted state.
A fifth aspect of the present invention provides a method of treating rosacea by administering to a person in need thereof a once daily pharmaceutical composition comprising doxycycline, a controlled-release polymer, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition contains up to 40 mg of doxycycline.
The term “doxycycline,” as used herein, includes doxycycline base and its pharmaceutically acceptable salts, hydrates, solvates, esters, or prodrugs. The preferred forms are the monohydrate form and the hyclate form.
The term “bioavailability,” as used herein, refers to the fraction of a drug that reaches systemic circulation after oral administration. Parameters used in the measurement of bioavailability are Cmax (maximum plasma concentration), AUC0-t (area under the curve), and Tmax (time to reach maximum plasma concentration), which are well known in the art.
The term “food effect,” as used herein, refers to the relative difference in AUC0-t and Cmax of a drug when it is administered in a fed state as compared to when it is administered in a fasted state.
The term “reduced food effect,” as used herein, refers to a state wherein food decreases Cmax and AUC0-t by less than 40% and 20%, respectively, in a fed state when compared to Cmax and AUC0-t in a fasted state.
The term “fasted state,” as used herein, refers to a gap of at least two hours between the meal and administration of the pharmaceutical composition.
The term “fed state,” as used herein, refers to administration from about 1 hour before a meal to about 1 hour after a meal.
The term “immediate-release portion,” as used herein, refers to that portion of the pharmaceutical composition which releases the drug immediately upon contact with gastric juices.
The term “controlled-release portion,” as used herein, refers to that portion of the pharmaceutical composition which contains a controlled-release polymer and releases the drug in a controlled manner over a period of time. Controlled-release can also be referred to as sustained release (SR), prolonged release (PR), or extended release (ER).
Suitable controlled-release polymers are selected from the group comprising hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl ethyl cellulose, ethyl cellulose, cellulose acetate, cellulose nitrate, polymethacrylic copolymer, poloxamers, polyoxyethylene stearate, polyvinyl pyrrolidone, polyvinyl pyrrolidone-polyvinylacetate copolymer, polyvinyl alcohol, polyethylene oxide, gums (e.g., xanthan gum, tragacanth gum, gum karaya, guar gum, acacia gum, and locust bean gum), fatty acids, fatty acid esters, alkyl alcohols, wax, shellac, and mixtures thereof.
The term “pharmaceutically acceptable excipients,” as used herein, includes any physiologically inert additives that are routinely used in pharmaceutical compositions. Pharmaceutically acceptable excipients are selected from the group comprising binders, diluents, disintegrants, lubricants/glidants/antiadherants, acidifying agents, and mixtures thereof.
Examples of binders include povidone, copovidone, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, xanthan gum, gum acacia, gum arabic, tragacanth, sorbitol, dextrose, sucrose, mannitol, gelatin, pullulan, sodium alginate, calcium alginate, ammonium calcium alginate, propylene glycol, polyvinyl alcohol, corn syrup, methacrylates, carboxyvinyl polymers, e.g., carbomers, and mixtures thereof.
Examples of diluents include microcrystalline cellulose, powdered cellulose, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium carbonate, lactose monohydrate, lactose anhydrous, sucrose, sorbitol, xylitol, erythritol, kaolin, calcium silicate, maltodextrin, starch, modified starch (e.g., pregelatinized starch, maize starch, and corn starch), and mixtures thereof.
Examples of disintegrants include hydroxypropyl cellulose (L-HPC), crospovidone, croscarmellose sodium, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, sodium starch glycolate, gums, alginic acid or alginates, starch, corn starch, modified starch, carboxymethyl starch, polyacrylates, and mixtures thereof.
Examples of lubricants/glidants/antiadherents include magnesium stearate, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, stearic acid, sodium stearyl fumarate, calcium stearate, zinc stearate, aluminum silicate, talc, colloidal silicon dioxide, sucrose esters of fatty acids, waxes, silica gel, and mixtures thereof.
Acidifying agents are pH modifiers which provide an acidic environment required for stability of the drug. Examples of acidifying agents include citric acid, tartaric acid, adipic acid, fumaric acid, malic acid, acetic acid, lactic acid, hydrochloric acid, phosphoric acid, and mixtures thereof.
Various solvents that may be employed during the preparation of the pharmaceutical composition of the present invention are selected from the group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, and mixtures thereof.
The pharmaceutical composition of the present invention may be prepared by any of the well-known processes including wet granulation, dry granulation, direct compression, top spray granulation, and drug layering. The immediate-release portion and the controlled-release portion may be in the form of pellets, beads, beadlets, granules, spheres or spheroids, minitablets, particles, or powders.
The pharmaceutical composition may be further coated with a film coating prepared by using a film-forming polymer and one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may be plasticizers, opacifiers, coloring agents, and mixtures thereof.
Examples of film-forming polymers include hydroxypropylmethyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropylmethyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers (e.g., Eudragit®), polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and mixtures thereof. A preferred film-forming polymer is hydroxypropylmethyl cellulose. Other suitable film-forming polymers which are known in the art may also be used. Alternatively, commercially available coating for pharmaceutical compositions comprising film-forming polymers marketed under various trade names, such as Opadry® and Opaglos®, may also be used.
Examples of plasticizers include propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, acetyl tributyl citrate, glyceryl monostearate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, diacetylated monoglycerides, cetyl alcohol, and mixtures thereof.
Examples of opacifiers include titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, and mixtures thereof.
The coloring agents may be selected from FDA approved colorants such as iron oxide, lake of tartrazine, allura red, titanium dioxide, and mixtures thereof.
The coating may be carried out by using any conventional coating techniques known in the art, such as spray coating in a conventional coating pan or fluidized bed processor, or dip coating.
The following examples illustrate the present invention but are not to be construed as limiting the scope of the invention.
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A bioavailability study was carried out to compare the doxycycline pharmaceutical composition prepared as per Example 1 of the present invention with Oracea® 40 mg capsules in healthy subjects under fasted and fed states. Table 1 provides the results of this study.
The data in Table 1 demonstrates that the pharmaceutical composition prepared as per the present invention has a reduced food effect wherein Cmax decreases by 19% and AUC0-t is almost unchanged (˜−7%), as compared to the reference product Oracea® which shows decreases in Cmax and AUC0-t by 45% and 22%, respectively, when taken along with food.
Another bioavailability study was carried out to compare the doxycycline pharmaceutical composition prepared as per Example 2 of the present invention with Oracea® 40 mg capsules in healthy subjects under fasted and fed states. Table 2 provides the results of this study.
The data in Table 2 demonstrates that the pharmaceutical composition prepared as per the present invention has a reduced food effect wherein Cmax decreases by 27% and AUC0-t is almost unchanged (˜−6%), as compared to the reference product Oracea® which shows decreases in Cmax and AUC0-t by 45% and 22%, respectively, when taken along with food.
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| Number | Date | Country | Kind |
|---|---|---|---|
| 791/DEL/2015 | Mar 2015 | IN | national |
This application is a continuation-in-part of U.S. application Ser. No. 14/821,263, filed on Aug. 7, 2015 (pending). U.S. application Ser. No. 14/821,263 is a continuation-in-part of U.S. application Ser. No. 14/326,949, filed on Jul. 9, 2014 (now U.S. Pat. No. 9,132,092). This application is a continuation of U.S. application Ser. No. 14/821,280, filed on Aug. 7, 2015 (pending). U.S. application Ser. No. 14/821,280 is a continuation-in-part of U.S. application Ser. No. 14/548,915, filed on Nov. 20, 2014 (pending).
| Number | Name | Date | Kind |
|---|---|---|---|
| 7749532 | Chang et al. | Jul 2010 | B2 |
| 8652516 | Etchegaray et al. | Feb 2014 | B1 |
| 9132092 | Sharma | Sep 2015 | B1 |
| Entry |
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| Agwuh et al., “Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines,” Journal of Antimicrobial Chemotherapy, 58(2):256-265 (2006). |
| Number | Date | Country | |
|---|---|---|---|
| 20160151397 A1 | Jun 2016 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14821280 | Aug 2015 | US |
| Child | 15013122 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14821263 | Aug 2015 | US |
| Child | 15013122 | US | |
| Parent | 14326949 | Jul 2014 | US |
| Child | 14821263 | US | |
| Parent | 15013122 | US | |
| Child | 14821263 | US | |
| Parent | 14548915 | Nov 2014 | US |
| Child | 14821280 | US |
