Patent Application
20160143924
The present invention relates to a low dose pharmaceutical composition of doxycycline comprising 24 mg to 36 mg of doxycycline and one or more pharmaceutically acceptable excipients for the treatment of acne and/or rosacea, and processes for its preparation.
U.S. Pat. No. 8,652,516 discloses a pharmaceutical composition of doxycycline comprising a capsule, wherein the capsule is coated with a delayed-release layer which comprises about 4 mg to 6 mg of doxycycline and an immediate-release layer which comprises about 32 mg of doxycycline. This patent discloses 36 mg and 38 mg doxycycline capsule formulations which are bioequivalent to the reference product Oracea® 40 mg.
Doxycycline has gastrointestinal side effects which are dose related, such as gastrointestinal irritation. Thus, lowering the dose of doxycycline may reduce these side effects. The present inventors have prepared a pharmaceutical composition which further lowers the dose of doxycycline for the treatment of acne and/or rosacea.
The present invention is directed to a low dose pharmaceutical composition comprising 24 mg to 36 mg doxycycline which is effective in the treatment of acne and/or rosacea.
The present invention provides a low dose pharmaceutical composition of doxycycline comprising 24 mg to 36 mg of doxycycline and one or more pharmaceutically acceptable excipients for the treatment of acne and/or rosacea, and processes for its preparation.
A first aspect of the present invention provides a low dose pharmaceutical composition comprising 24 mg to 36 mg of doxycycline and one or more pharmaceutically acceptable excipients.
According to one embodiment of this aspect, the low dose pharmaceutical composition is intended for once daily administration.
According to another embodiment of the above aspect, the low dose pharmaceutical composition comprises 30 mg to 36 mg of doxycycline.
According to another embodiment of the above aspect, the low dose pharmaceutical composition comprises 32 mg to 36 mg of doxycycline.
According to another embodiment of the above aspect, the low dose pharmaceutical composition comprises 24 mg of doxycycline.
According to another embodiment of the above aspect, the low dose pharmaceutical composition comprises 26 mg of doxycycline.
According to another embodiment of the above aspect, the low dose pharmaceutical composition comprises 28 mg of doxycycline.
According to another embodiment of the above aspect, the low dose pharmaceutical composition comprises 30 mg of doxycycline.
According to another embodiment of the above aspect, the low dose pharmaceutical composition comprises 32 mg of doxycycline.
According to another embodiment of the above aspect, the low dose pharmaceutical composition comprises 34 mg of doxycycline.
According to another embodiment of the above aspect, the low dose pharmaceutical composition comprises 36 mg of doxycycline.
According to another embodiment of this aspect, the low dose pharmaceutical composition is an immediate release composition.
A second aspect of the present invention provides a method of treating acne and/or rosacea by administering a low dose pharmaceutical composition comprising 24 mg to 36 mg of doxycycline and one or more pharmaceutically acceptable excipients.
The pharmaceutical composition may be in the form of capsules or tablets. Preferably, the pharmaceutical composition is in the form of tablets.
The term “doxycycline,” as used herein, includes doxycycline base and its pharmaceutically acceptable salts, hydrates, solvates, esters, or prodrugs. Preferably, doxycycline is used as its hyclate salt, which is doxycycline hydrochloride hemiethanolate hemihydrate.
The term “low dose,” as used herein, refers to a dose of 24 mg to 36 mg doxycycline base, which is less than the conventional dose of 40 mg which is required to produce the therapeutic effect.
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. The pharmaceutically acceptable excipients may be added intragranularly as well as extragranularly.
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 like 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, 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 pharmaceutical composition of the present invention may be in the form of a tablet or a capsule. The tablet or capsule 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®, polyvinylpyrrolidone, polyvinylalcohol, 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. Many suitable film coating products which are commercially available, such as Opadry® and Opaglos®, may 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.
For the terms “for example” and “such as,” and grammatical equivalences thereof, the phrase “and without limitation” is understood to follow unless explicitly stated otherwise. As used herein, the term “about” is meant to account for variations due to experimental error. All measurements reported herein are understood to be modified by the term “about,” whether or not the term is explicitly used, unless explicitly stated otherwise. As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
The following examples illustrate the present invention but are not to be construed as limiting the scope of the invention.
Manufacturing process:
Doxycycline is virtually completely absorbed after oral administration. The comparison of intravenous and oral doses of doxycycline indicated lower absorption for oral administration in the range of 73% to 77% (Agwuh et al. “Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines,” Journal of Antimicrobial Chemotherapy, 58(2):256-265(2006)). This may be due to site specific absorption in the upper part of gastrointestinal tract (GIT), i.e., in the duodenum region. The drug released beyond the duodenum remains unabsorbed.
The same is indicated from bioequivalence studies carried out on two formulations. Example 12 having an immediate release (IR) component as 60% had shown lower bioavailability w.r.t. the reference product Oracea® having an IR component as 75% as indicated from the results shown in Table 1.
As doxycycline is absorbed from the upper part of the GIT, low bioavailability is observed in controlled release (CR) formulation which may be attributed to unabsorbed portion from the CR component.
The Cmax ratio, in fact, may also be empirically derived from the calculation of the ratio of IR contribution from both formulations (i.e., 60/75=0.8).
Thus, the IR component results in complete release and absorption of the drug.
Based on the above understanding, pharmacokinetic values were predicted for dosage forms containing 24 mg to 36 mg of only IR components. The bioequivalence criteria was calculated using software Phoenix 64 (WinNonlin 6.4). The results are shown in Table 2:
The data shows that formulations containing 24-36 mg of doxycycline would be similar to existing RLD (Oracea®) in terms of pharmacokinetic parameters of Cmax and/or AUC.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14548915 | Nov 2014 | US |
| Child | 14821280 | US |
