Protective coatings for moisture sensitive pharmaceutical compositions

Abstract

Pharmaceutical compositions and methods for preparing pharmaceutical compositions, including wax-coated tablets, are provided. Specifically, a wax coating can be applied to the pharmaceutical tablets prior to the film-coating process.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 197,880, filed June 7, 2021, the entire contents of which are incorporated herein by reference.

[0002] This relates to pharmaceutical compositions comprising coatings and methods for coating pharmaceutical compositions. In particular, this relates to wax coatings for pharmaceutical compositions and methods of applying wax coatings to pharmaceutical compositions. [Background technology]

[0003] A pharmaceutical composition typically contains both an active pharmaceutical ingredient and one or more inactive ingredients. An active pharmaceutical ingredient (API) may be biologically active and may be designed to directly affect a patient's symptoms, disease, disorder, and / or illness. On the other hand, an inactive ingredient of a pharmaceutical composition is pharmacologiciZably inactive and may be used for a variety of purposes, including, but not limited to, improving long-term stability, bulking or diluting a solid formulation, enhancing drug absorption, modifying the viscosity of a liquid formulation, enhancing solubility, and / or aiding in the manufacture of the pharmaceutical composition.

[0004] Many pharmaceutical compositions (e.g., dosage forms such as tablets) are coated with an aqueous film coating during the drug manufacturing process. However, aqueous film coating can pose challenges depending on the particular API and overall formulation of the pharmaceutical composition. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Provisional Patent Application No. 63 / 197,880 Summary of the Invention [Problem to be solved by the invention]

[0006] Some pharmaceutical compositions contain moisture-sensitive materials. For example, there are various APIs that are moisture-sensitive and can begin to degrade upon the introduction of water, which can occur during the film-coating process. This degradation of the API can result in a dosage form that is less potent, has a reduced shelf life, and / or compromises the critical quality attributes (CQAs) of the drug product.

[0007] Furthermore, some of the components of a pharmaceutical composition may be highly soluble. Thus, when a coating is applied to a pharmaceutical composition (e.g., a tablet), the pharmaceutical composition may begin to dissolve. This may result in defects in the film coating that may not be commercially acceptable. [Means for solving the problem]

[0008] Applicants have discovered that a pharmaceutical composition (e.g., tablet) can be first coated with a wax coating before starting the aqueous film coating. Applicants have found that this initial wax coating is not sufficient to affect the dissolution profile of the pharmaceutical composition tablet, but is sufficient to provide a protective barrier sufficient to allow the application of a base coat to the film coat without compromising the stability or integrity of the core tablet.

[0009] Carnauba wax has been used historically in the film coating process, but it is used after the film coat is applied to the tablet to increase the sheen / gloss of the coating, so the wax was used as an aesthetic choice rather than a functional use.

[0010] In some embodiments, the pharmaceutical composition comprises a tablet comprising an active pharmaceutical ingredient (API), a first coating on the surface of the tablet comprising a wax, and a second coating on the surface of the first coating comprising polyvinyl alcohol. In some embodiments, the wax comprises carnauba wax. In some embodiments, the pharmaceutical composition comprises 0.5-1.0% w / w of wax. In some embodiments, the first coating comprises a wax. In some embodiments, the second coating is an OPADRY® moisture barrier film coating. In some embodiments, the pharmaceutical composition comprises a third coating on the surface of the second coating, the third coating comprising an acrylic acid and / or an acrylate. In some embodiments, the third coating is an ACRYL-EZE® enteric coating. In some embodiments, the API comprises ALXN1840 or AKST4290. In some embodiments, the tablet comprises sodium bicarbonate.

[0011] In some embodiments, a method for preparing a pharmaceutical composition includes compressing a tablet containing an active pharmaceutical ingredient (API), coating the surface of the tablet with a first coating comprising a wax, and coating the surface of the first coating with a second coating comprising polyvinyl alcohol. In some embodiments, the step of coating the surface of the tablet with the first coating comprises coating the surface of the tablet with the first coating such that the tablet has a mass gain from the first coating of 0.5-1.0%. In some embodiments, the step of coating the surface of the first coating comprises coating the surface of the first coating such that the tablet and the first coating have a mass gain from the second coating of 1-30%. In some embodiments, the tablet and the first coating have a mass gain from the second coating of 15-25%. In some embodiments, the wax comprises carnauba wax. In some embodiments, the first coating comprises a wax. In some embodiments, the second coating is an OPADRY® moisture barrier film coating. In some embodiments, the method includes coating the surface of the second coating with a third coating comprising acrylic acid and / or an acrylate. In some embodiments, the third coating is an ACRYL-EZE® enteric coating. In some embodiments, the API comprises ALXN1840 or AKST4290. In some embodiments, the tablet comprises sodium bicarbonate.

[0012] Further advantages will become readily apparent to those skilled in the art from the following detailed description.The examples and descriptions herein are to be regarded as illustrative in nature and not as limiting.

[0013] All publications, including patent documents, scientific articles, and databases, referenced in this application are incorporated by reference in their entirety and for all purposes to the same extent as if each individual publication was individually incorporated by reference. To the extent that the definitions set forth herein conflict or are otherwise inconsistent with the definitions set forth in the patents, applications, published applications, and other publications incorporated herein by reference, the definitions set forth herein shall take precedence over the definitions incorporated herein by reference. [Brief description of the drawings]

[0014] [Figure 1A] FIG. 1 illustrates a tablet coated with a film coating without a wax coating according to some embodiments disclosed herein. [Figure 1B] FIG. 1 illustrates a further tablet coated with a film coating that does not include a wax coating, according to some embodiments disclosed herein. [Diagram 2] FIG. 2A shows a side view of an uncoated tablet and a tablet coated with a film and an enteric coating according to some embodiments disclosed herein. FIG. 2B shows a top view of an uncoated tablet and a tablet coated with a film and an enteric coating according to some embodiments disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Described herein are exemplary embodiments of pharmaceutical compositions and methods for coating pharmaceutical compositions to provide a protective barrier to the pharmaceutical composition and / or API. Prior to aqueous film coating, the pharmaceutical composition can be coated with a wax coating that does not impair the stability or integrity of the pharmaceutical composition.

[0016] The pharmaceutical composition may include a dosage form such as a tablet, which includes an active pharmaceutical ingredient and a number of other ingredients that make up the tablet. The pharmaceutical composition may also include a wax coating on the surface of the tablet, and any subsequent coatings on the tablet. Thus, as used herein below, the pharmaceutical composition may refer to the tablet and any coatings applied to the tablet.

[0017] Tablets can be made by various methods such as wet granulation, dry granulation, or direct compression. Wet granulation typically includes the steps of (1) mixing the API with other ingredients to form a powder, (2) preparing a binder solution, (3) mixing the binder solution with the powder, (4) screening the wet powder into pellets / granules, (5) drying the pellets / granules, (6) sizing the granulation by dry screening, (7) mixing the dried pellets / granules with a lubricant and disintegrant, and / or (8) compressing the pellets / granules into tablets. Dry granulation typically includes the steps of (1) mixing the API with other ingredients to form a powder, (2) compressing the powder into slugs, (3) milling / sieving the slugs, (4) mixing the slugs with a lubricant and disintegrant, and / or (5) compressing into tablets. Direct compression typically involves (1) mixing the API with other ingredients (including disintegrants and lubricants) and (2) compressing the powder into a tablet.

[0018] Any API may be used with the pharmaceutical compositions disclosed herein. Those skilled in the art will appreciate that certain active ingredients and / or APIs are more desirable for formulation into dosage forms for various reasons, such as stability, compatibility with other ingredients, desired drug release profile, etc. In some embodiments, the API may be an active pharmaceutical ingredient for the treatment of a human or veterinary disease. The API may be the ingredient that the solid dosage form is used to deliver. The API may be one or more of antibacterial agents, antifungals, antiprotozoal agents, antivirals, labor inducers, spermicides, prostaglandins, steroids and bactericides, proteins / peptides, and vaccine antigens.

[0019] APIs may include pharmaceutical ingredients and other types of ingestible active ingredients, such as vitamins and dietary supplements. Suitable APIs include, without limitation, analgesics and anti-inflammatory agents (e.g., ibuprofen), antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antianxiety antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigouts, antihypertensives, antimalarials, migraine medications, antimuscarinics, antineoplastics and immunosuppressants, antiprotozoal drugs, antirheumatic drugs, antithyroid drugs, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics, beta-glucosamines, sedatives, hypnotics and neuroleptics, and antispasmodics. -blockers, cardiac inotropes, corticosteroids, antitussives, cytotoxics, decongestants, diuretics, enzymes, antiparkinsonian drugs, gastrointestinal drugs, histamine receptor antagonists, lipid regulating drugs, local anesthetics, neuromuscular agents, nitrates and antianginal drugs, nutritionals, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, smoking cessation products, and combinations thereof.

[0020] An API may be a single active pharmaceutical ingredient, e.g., a single chemical entity, or it may be a mixture of several active pharmaceutical ingredients. The active pharmaceutical ingredient may be any of a number of categories of active pharmaceutical ingredients.Active pharmaceutical ingredients include, but are not limited to, acyclovir, fluconazole, progesterone and its derivatives, nonoxylenol-9, terbutaline, lidocaine, testosterone and derivatives, dinoprostone, lactobacillus, estrogen and derivatives, naphthalene 2-sulfonate, resmitidan, doxycycline, droxidopa, sapropterin, butoconazole, clindamycin nitrate / phosphate, neomycin sulfate, sulfate, polymyxin sulfate, nystatin, clotrimazole, dextrin sulfate, glyminox, miconazole nitrate, benzalkonium chloride, sodium lauryl sulfate, tenofovir, insulin, calcitonin, danazol, ibuprofen, acetaminophen, cefpodoxime proxetil, desloratadine, dextromethorphan, diphenhydramine hydrochloride, vitamins and / or minerals, adipic acid, ascorbic acid, macrolide antibiotics, NS-AIDS, cefuroxime axetil, amobarbital, ciprofloxacin hydrochloride, sildenafil citrate, pinaverium bromide, propantheline bromide, triprolidine Hcl, dimenhydrinate, cefacanel daroxate daloxate HCl, enoxacin, sparfloxacin, aspirin, famotidine, amoxycilin trihydrate, morphine HCl, amiprilose HCl, terfenadine, beclamide, clarithromycin, roxithromycin, nizatidine, cetraxate HCl, ciprofloxacin, bifemelene HCl, cefuroxime axetil, pirienzepine and / or oxyburynin, diclofenac, nicorandil, levofloxacin, acriflavine, leuprorelin acetate, metronidazole, benzydamine hydrochloride, chloramphenicol, oxybutynin, ethinyl estradiol, prostaglandins, insulin, calcitonin, and combinations thereof.The active pharmaceutical ingredient may also be a vaccine antigen, e.g., for the treatment of Hepatitis B, HIV, HPV, Chlamydia, Gonorrhea infection. In some embodiments, the API may be ALXN1840 or AKST4290.

[0021] The API may include salts, esters, hydrates, solvates, and derivatives of any of the above active ingredients. Suitable derivatives are known to those skilled in the art to have the same activity as the active ingredient, but the activity level may be lower or higher. The API may also include any active ingredient that is incompatible with oral delivery methods or compositions.

[0022] If present, the API is used in the formulation to provide the required dosage, typically in an effective amount necessary to produce at least one physiological effect as established by clinical studies. One of ordinary skill in the art can readily determine the appropriate amount of active ingredient to include in a dosage form (e.g., tablet) made according to the present disclosure.

[0023] In some embodiments, the tablet of the pharmaceutical composition may comprise about 1-20%, about 1-15%, about 5-10%, about 7-9%, or about 8-9% of the API by weight. In some embodiments, the tablet of the pharmaceutical composition may comprise at least about 1%, at least about 5%, at least about 8%, at least about 10%, at least about 15%, or at least about 20% of the API by weight. In some embodiments, the tablet of the pharmaceutical composition may comprise up to about 30%, up to about 25%, up to about 20%, up to about 15%, up to about 10%, or up to about 9% of the API by weight. In some embodiments, the pharmaceutical composition (including any coatings) may comprise about 1-20%, about 1-15%, about 2-8%, about 3-8%, or about 4-6% of the API by weight. In some embodiments, the pharmaceutical composition (including any coatings) may comprise at least 1% by weight of the API, at least 2% by weight of the API, at least 3% by weight of the API, at least 4% by weight of the API, or at least 5% by weight of the API, hi some embodiments, the pharmaceutical composition (including any coatings) may comprise up to about 20% by weight, up to about 15% by weight, or up to about 10% by weight of the API.

[0024] In some embodiments, the tablet of the pharmaceutical composition may comprise about 50-90%, about 60-80%, about 60-75%, about 60-70%, or about 65-70% of the API by weight. In some embodiments, the tablet of the pharmaceutical composition may comprise at least 50%, at least 55%, at least 60%, or at least 65% of the API by weight. In some embodiments, the tablet of the pharmaceutical composition may comprise up to 90%, up to 85%, up to 80%, up to 75%, or up to 70% of the API by weight. In some embodiments, the pharmaceutical composition (including any coatings) may comprise about 50-90%, about 60-80%, about 60-75%, about 60-70%, or about 63-67% of the API by weight. In some embodiments, the pharmaceutical composition (including any coatings) may comprise at least 50%, at least 55%, at least 60%, or at least 64% of the API by weight. In some embodiments, the pharmaceutical composition (including any coatings) comprises up to 90% by weight, up to 85% by weight, up to 80% by weight, up to 75% by weight, or up to 70% by weight of the API.

[0025] In some embodiments, the tablet comprises about 50-99%, about 55-99%, or about 60-99% by weight of the pharmaceutical composition. In some embodiments, the tablet comprises at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% by weight of the pharmaceutical composition. In some embodiments, the tablet comprises up to 99%, up to 98%, up to 97%, up to 95%, up to 90%, up to 85%, up to 80%, up to 75%, up to 70%, or up to 65% by weight of the pharmaceutical composition.

[0026] In some embodiments, the pharmaceutical composition tablet may include an API stabilizer. In some embodiments, the API stabilizer may stabilize the API by maintaining the pH at a certain level. For example, the API stabilizer may prevent the API from becoming acidic. In some embodiments, the API stabilizer may be sodium bicarbonate, citric acid, fumaric acid, malic acid, potassium bicarbonate, sodium carbonate, sodium citrate dihydrate, and / or tartaric acid. In some embodiments, the pharmaceutical composition tablet may include about 15-35%, about 20-30%, or about 23-27% API stabilizer by weight. In some embodiments, the pharmaceutical composition tablet may include at least about 15%, at least about 20%, or at least about 25% API stabilizer by weight. In some embodiments, the pharmaceutical composition tablet may include up to about 40%, up to about 35%, or up to about 30% API stabilizer by weight. In some embodiments, the pharmaceutical composition (including any coatings) comprises about 5-25%, about 10-20%, or about 13-17% API stabilizer by weight. In some embodiments, the pharmaceutical composition (including any coatings) comprises at least about 5%, at least about 10%, or at least about 15% API stabilizer by weight. In some embodiments, the pharmaceutical composition (including any coatings) comprises up to about 30%, up to about 25%, or up to about 20% API stabilizer by weight.

[0027] In some embodiments, the tablet of the pharmaceutical composition includes a binder. In some embodiments, the binder can also be a diluent. In some embodiments, the binder can be a cellulose (e.g., microcrystalline cellulose (e.g., Avicel PH 112)), dextrates, starch, calcium carbonate, and / or dextrose. In some embodiments, the tablet of the pharmaceutical composition can include about 55-75%, about 60-70%, or about 63-67% by weight of binder. In some embodiments, the tablet of the pharmaceutical composition can include at least about 55%, at least about 60%, or at least about 65% by weight of binder. In some embodiments, the tablet of the pharmaceutical composition can include up to about 80%, up to about 75%, or up to about 70% by weight of binder. In some embodiments, the pharmaceutical composition (including any coating) includes about 30-50%, about 35-45%, or about 38-42% by weight of binder. In some embodiments, the pharmaceutical composition (including any coatings) comprises at least about 30%, at least about 35%, or at least about 40% by weight of the binder, hi some embodiments, the pharmaceutical composition (including any coatings) comprises up to about 55%, up to about 50%, or up to about 45% by weight of the binder.

[0028] In some embodiments, the tablet of the pharmaceutical composition may comprise about 1-10%, about 2-8%, or about 4-8% by weight of the binder. In some embodiments, the tablet of the pharmaceutical composition may comprise at least about 1%, at least about 2%, or at least about 5% by weight of the binder. In some embodiments, the tablet of the pharmaceutical composition may comprise up to about 15%, up to about 10%, or up to about 8% by weight of the binder. In some embodiments, the pharmaceutical composition (including any coatings) comprises about 1-10%, about 2-8%, or about 4-8% by weight of the binder. In some embodiments, the pharmaceutical composition (including any coatings) comprises at least about 1%, at least about 3%, or at least about 5% by weight of the binder. In some embodiments, the pharmaceutical composition (including any coatings) comprises up to about 15%, up to about 10%, or up to about 8% by weight of the binder.

[0029] In some embodiments, the tablet of the pharmaceutical composition may comprise about 1-25%, about 5-20%, or about 10-15% by weight of the diluent. In some embodiments, the diluent is a water-soluble diluent. In some embodiments, the diluent may be lactose (e.g., anhydrous lactose), mannitol, maltose, sorbitol, various grades of MCC, dicalcium phosphate, and / or starch (e.g., pregelatinized starch). In some embodiments, the tablet of the pharmaceutical composition may comprise at least about 1%, at least about 5%, or at least about 10% by weight of the diluent. In some embodiments, the tablet of the pharmaceutical composition may comprise up to about 25%, up to about 20%, or up to about 15% by weight of the diluent. In some embodiments, the pharmaceutical composition (including any coating) comprises about 1-25%, about 5-20%, or about 10-15% by weight of the diluent. In some embodiments, the pharmaceutical composition (including any coatings) comprises at least about 1%, at least about 5%, or at least about 10% by weight of the diluent, hi some embodiments, the pharmaceutical composition (including any coatings) comprises up to about 25%, up to about 20%, or up to about 15% by weight of the diluent.

[0030] In some embodiments, the tablet of the pharmaceutical composition may comprise about 0.1-1%, about 0.1-0.5%, or about 0.2-0.3% by weight of a lubricant. In some embodiments, the lubricant may be colloidal silicon dioxide, magnesium carbonate, talc, and / or calcium silicate. In some embodiments, the colloidal silicon dioxide may be aerosil 200. In some embodiments, the tablet of the pharmaceutical composition may comprise at least about 0.1%, at least about 0.15%, or at least about 0.2% by weight of a lubricant. In some embodiments, the tablet of the pharmaceutical composition may comprise up to about 1%, up to about 0.5%, or up to about 0.3% by weight of a lubricant. In some embodiments, the pharmaceutical composition (including any coatings) comprises about 0.1-1%, about 0.1-0.5%, or about 0.2-0.3% by weight of a lubricant. In some embodiments, the pharmaceutical composition (including any coatings) comprises at least about 0.1%, at least about 0.15%, or at least about 0.2% by weight of a lubricant, hi some embodiments, the pharmaceutical composition (including any coatings) comprises up to about 1%, up to about 0.5%, or up to about 0.3% by weight of a lubricant.

[0031] In some embodiments, tablets may include intragranular and extragranular components. The intragranular components may be roller-compacted and / or wet-compressed components. The extragranular components may be components added after granulation.

[0032] In some embodiments, the tablet of the pharmaceutical composition may comprise about 1-10%, about 2-8%, or about 3-7% by weight of superdisintegrant (intragranular). In some embodiments, the superdisintegrant (intragranular) may be croscarmellose sodium (intragranular) (e.g., croscarmellose sodium NF. Ph. Eur., JP (Ac-Di-Sol)), sodium starch glycolate (intragranular) and / or crospovidone (intragranular). In some embodiments, the tablet of the pharmaceutical composition may comprise at least about 1%, at least about 2%, or at least about 3% by weight of superdisintegrant (intragranular). In some embodiments, the tablet of the pharmaceutical composition may comprise up to about 10%, up to about 8%, or up to about 6% by weight of superdisintegrant (intragranular). In some embodiments, the pharmaceutical composition (including any coating) comprises about 1-10%, about 2-8%, or about 3-7% by weight of superdisintegrant (intragranular). In some embodiments, the pharmaceutical composition (including any coatings) comprises at least about 1%, at least about 2%, or at least about 3% by weight of superdisintegrant (intragranular).In some embodiments, the pharmaceutical composition (including any coatings) comprises up to about 10%, up to about 7%, or up to about 5% by weight of superdisintegrant (intragranular).

[0033] In some embodiments, the tablet of the pharmaceutical composition may comprise about 1-10%, about 2-8%, or about 3-7% by weight of superdisintegrant (extragranular). In some embodiments, the superdisintegrant (extragranular) may be croscarmellose sodium (extragranular) (e.g., croscarmellose sodium NF. Ph. Eur., JP (Ac-Di-Sol)), sodium starch glycolate (extragranular) or crospovidone (extragranular). In some embodiments, the tablet of the pharmaceutical composition may comprise at least about 1%, at least about 2%, or at least about 3% by weight of superdisintegrant (extragranular). In some embodiments, the tablet of the pharmaceutical composition may comprise up to about 10%, up to about 8%, or up to about 6% by weight of superdisintegrant (extragranular). In some embodiments, the pharmaceutical composition (including any coating) comprises about 1-10%, about 2-8%, or about 3-7% by weight of superdisintegrant (extragranular). In some embodiments, the pharmaceutical composition (including any coatings) comprises at least about 1%, at least about 2%, or at least about 3% by weight of superdisintegrant (extragranular).In some embodiments, the pharmaceutical composition (including any coatings) comprises up to about 10%, up to about 7%, or up to about 5% by weight of superdisintegrant (extragranular).

[0034] In some embodiments, the tablet of the pharmaceutical composition may include about 0.1-3%, about 0.2-2.5%, or about 0.25-1.5% by weight of lubricant (intragranular). In some embodiments, the lubricant may be sodium stearyl fumarate (intragranular), stearic acid (intragranular), compritol (intragranular), calcium stearate (intragranular), and / or magnesium stearate (intragranular). In some embodiments, the tablet of the pharmaceutical composition may include at least about 0.1%, at least about 0.2%, at least about 0.25%, at least about 0.5%, at least about 1%, or at least about 1.5% by weight of lubricant (intragranular). In some embodiments, the tablet of the pharmaceutical composition may include up to about 3%, up to about 2%, up to about 1.5%, up to about 1%, or up to about 0.5% by weight of lubricant (intragranular). In some embodiments, the pharmaceutical composition (including all coatings) comprises about 0.1-3%, about 0.1-2.5%, or about 0.15-1.5% by weight of lubricant (intragranular). In some embodiments, the pharmaceutical composition (including all coatings) comprises at least about 0.1%, at least about 0.15%, at least about 0.2%, at least about 0.3%, at least about 0.5%, or at least about 1% by weight of lubricant (intragranular). In some embodiments, the pharmaceutical composition (including all coatings) comprises up to about 3%, up to about 2%, up to about 1.5%, up to about 1%, or up to about 0.5% by weight of lubricant (intragranular).

[0035] In some embodiments, the tablet of the pharmaceutical composition may include about 0.1-3%, about 0.2-2.5%, or about 0.25-1.5% by weight of lubricant (extragranular). In some embodiments, the lubricant (extragranular) may be sodium stearyl fumarate (extragranular), stearic acid (extragranular), compritol (extragranular), calcium stearate (intragranular), and / or magnesium stearate (extragranular). In some embodiments, the tablet of the pharmaceutical composition may include at least about 0.1%, at least about 0.2%, at least about 0.25%, at least about 0.5%, at least about 1%, or at least about 1.5% by weight of lubricant (extragranular). In some embodiments, the tablet of the pharmaceutical composition may include up to about 3%, up to about 2%, up to about 1.5%, up to about 1%, or up to about 0.5% by weight of lubricant (extragranular). In some embodiments, the pharmaceutical composition (including all coatings) comprises about 0.1-3%, about 0.1-2.5%, or about 0.15-1.5% lubricant (extragranular) by weight. In some embodiments, the pharmaceutical composition (including all coatings) comprises at least about 0.1%, at least about 0.15%, at least about 0.2%, at least about 0.3%, at least about 0.5%, or at least about 1% lubricant (extragranular) by weight. In some embodiments, the pharmaceutical composition (including all coatings) comprises up to about 3%, up to about 2%, up to about 1.5%, up to about 1%, or up to about 0.5% lubricant (extragranular) by weight.

[0036] In some embodiments, the tablet of the pharmaceutical composition may comprise about 0.1-2%, about 0.3-1.5%, or about 0.5-1% by weight of surfactant (intragranular). In some embodiments, the surfactant (intragranular) may be sodium lauryl sulfate (intragranular), carbowax PEG 3350 Sentry powder (or other PEG variants) (intragranular), poloxamer (various grades) (intragranular), and / or polysorbate (various grades) (intragranular). In some embodiments, the tablet of the pharmaceutical composition may comprise at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.5%, at least about 0.7%, or at least about 0.75% by weight of surfactant (intragranular). In some embodiments, the tablet of the pharmaceutical composition may comprise up to about 2%, up to about 1.5%, up to about 1%, up to about 0.9%, or up to about 0.8% by weight of surfactant (intragranular). In some embodiments, the pharmaceutical composition (including all coatings) comprises about 0.1-2%, about 0.3-1.5%, or about 0.5-1% by weight of surfactant (intragranular). In some embodiments, the pharmaceutical composition (including all coatings) comprises at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.5%, at least about 0.7%, or at least about 0.75% by weight of surfactant (intragranular). In some embodiments, the pharmaceutical composition (including all coatings) comprises up to about 2%, up to about 1.5%, up to about 1%, up to about 0.9%, or up to about 0.8% by weight of surfactant (intragranular).

[0037] In some embodiments, the tablet of the pharmaceutical composition may comprise about 0.1-2%, about 0.3-1.5%, or about 0.5-1% by weight of surfactant (extragranular). In some embodiments, the surfactant (extragranular) may be sodium lauryl sulfate (extragranular), carbowax PEG 3350 Sentry powder (or other PEG variants) (extragranular), poloxamer (various grades) (extragranular), and / or polysorbate (various grades) (extragranular). In some embodiments, the tablet of the pharmaceutical composition may comprise at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.5%, at least about 0.7%, or at least about 0.75% by weight of surfactant (extragranular). In some embodiments, the tablet of the pharmaceutical composition may comprise up to about 2%, up to about 1.5%, up to about 1%, up to about 0.9%, or up to about 0.8% by weight of surfactant (extragranular). In some embodiments, the pharmaceutical composition (including all coatings) comprises about 0.1-2%, about 0.3-1.5%, or about 0.5-1% by weight of surfactant (extragranular). In some embodiments, the pharmaceutical composition (including all coatings) comprises at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.5%, at least about 0.7%, or at least about 0.75% by weight of surfactant (extragranular). In some embodiments, the pharmaceutical composition (including all coatings) comprises up to about 2%, up to about 1.5%, up to about 1%, up to about 0.9%, or up to about 0.8% by weight of surfactant (extragranular).

[0038] In some embodiments, the tablet of the pharmaceutical composition may comprise about 0.1-1%, about 0.1-0.5%, or about 0.2-0.3% by weight of the second lubricant (intragranular). In some embodiments, the second lubricant (intragranular) may be any lubricant disclosed herein. In some embodiments, the tablet of the pharmaceutical composition may comprise at least about 0.1%, at least about 0.15%, or at least about 0.2% by weight of the second lubricant (intragranular). In some embodiments, the tablet of the pharmaceutical composition may comprise up to about 1%, up to about 0.5%, or up to about 0.3% by weight of the second lubricant (intragranular). In some embodiments, the pharmaceutical composition (including any coating) comprises about 0.1-1%, about 0.1-0.5%, or about 0.2-0.3% by weight of the second lubricant (intragranular). In some embodiments, the pharmaceutical composition (including any coatings) comprises at least about 0.1%, at least about 0.15%, or at least about 0.2% by weight of a second lubricant (intragranular). In some embodiments, the pharmaceutical composition (including any coatings) comprises up to about 1%, up to about 0.5%, or up to about 0.3% by weight of a second lubricant (intragranular).

[0039] In some embodiments, the tablet of the pharmaceutical composition may comprise about 0.1-1%, about 0.1-0.5%, or about 0.2-0.3% by weight of a second lubricant (extragranular). In some embodiments, the second lubricant (extragranular) may be any lubricant disclosed herein. In some embodiments, the tablet of the pharmaceutical composition may comprise at least about 0.1%, at least about 0.15%, or at least about 0.2% by weight of a second lubricant (extragranular). In some embodiments, the tablet of the pharmaceutical composition may comprise up to about 1%, up to about 0.5%, or up to about 0.3% by weight of a second lubricant (extragranular). In some embodiments, the pharmaceutical composition (including any coating) comprises about 0.1-1%, about 0.1-0.5%, or about 0.2-0.3% by weight of a second lubricant (extragranular). In some embodiments, the pharmaceutical composition (including any coatings) comprises at least about 0.1%, at least about 0.15%, or at least about 0.2% by weight of a second lubricant (extragranular).In some embodiments, the pharmaceutical composition (including any coatings) comprises up to about 1%, up to about 0.5%, or up to about 0.3% by weight of a second lubricant (extragranular).

[0040] As explained above, tablets having the compositions disclosed above can be formed from either wet granulation, dry granulation, or direct compression. Once the tablets are formed, they can be coated with a first coating that directly coats the surface of the tablet. This first coating can be a wax coating. The wax in the wax coating can be carnauba wax, beeswax, and other waxes. In some embodiments, coating can be accomplished by Vector Coater, Compu-Lab 24, Compu-Lab 35, and / or Accela Cota Coaters with various size pans (e.g., 15", 19" pans).

[0041] As mentioned above, applicants have discovered that a small amount of wax can provide a sufficient protective barrier to be applied to the film coat without affecting the dissolution profile of the tablet or compromising the stability / integrity of the tablet. In some embodiments, the wax coating can be applied as a 0.5-1.0% mass gain to the tablet itself. For example, if the tablet weighs 15 mg, a 1% mass gain would add 0.15 mg of wax to the tablet. In some embodiments, the wax coating can be applied as about a 0.1-2% mass gain, about a 0.3-1.5% mass gain, or about a 0.5-1.0% mass gain to the tablet. In some embodiments, the amount of wax + wax coating in the tablet can be about 0.1-2% by weight, about 0.3-1.5% by weight, or about 0.5-1% by weight. In some embodiments, the amount of wax plus wax coating in the tablet may be at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, or at least about 0.8% by weight. In some embodiments, the amount of wax plus wax coating in the tablet may be up to about 2%, up to about 1.5%, up to about 1%, up to about 0.9%, or up to about 0.8% by weight. In some embodiments, the amount of wax in the pharmaceutical composition (including any coatings) comprises about 0.1-2%, about 0.3-1.5%, or about 0.5-1% by weight. In some embodiments, the amount of wax in the pharmaceutical composition (including any coatings) may be at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, or at least about 0.8% by weight. In some embodiments, the amount of wax in the pharmaceutical composition (including any coatings) may be up to about 2%, up to about 1.5%, up to about 1%, up to about 0.9%, or up to about 0.8% by weight.

[0042] In some embodiments, the wax coating can be applied to the tablets by the following method: After the tablets are sufficiently heated (e.g., when the bed pan achieves a temperature of greater than about 20°C, greater than about 25°C, greater than about 30°C, greater than about 35°C, greater than about 40°C, or greater than about 45°C and less than about 50°C, less than about 45°C, less than about 40°C, less than about 35°C, less than about 30°C, or less than about 25°C), the intake and exhaust blowers can be stopped and a predetermined appropriate aliquot of wax can be added slowly (e.g., over approximately 2-5 minutes) to the pan and spread on top of the core tablets by the rotation of the pan. In some embodiments, a wax paper sheet can be placed under the pan. In some embodiments, the wax from the wax paper can be collected and spread on top of the core tablets. The speed of the pan can be adjusted based on visual observation of the tablet bed. The tablets can be rolled with the wax at about 3 RPM for about 5-10 minutes. After 5-10 minutes, the exhaust blower may be turned on and run for an additional 3-7 minutes. The intake blower may also be turned on and run for an additional 3-7 minutes. The wax-coated tablets may then be removed for further processing.

[0043] After the tablets are coated with a layer of wax, they can be film coated. Film coating can include deposition of a film-forming polymer onto the wax coating. Typically, the film coating formulation can include a polymer (e.g., polyvinyl alcohol) solubilized in a suitable solvent along with other additives such as plasticizers and pigments / colorants. Examples of film coatings can include OPADRY® moisture barrier film coatings, such as OPADRY® AMBII, OPADRY® 200, OPADRY® II, and / or OPADRY® QX (any Opadry series). The film coating formulation can be sprayed onto a rotating or fluidized tablet bed. The drying conditions of the film coating process can remove the solvent, leaving a thin layer of coating material around the wax tablet.

[0044] In some embodiments, the film coating may be prepared as a solid suspension and applied to the wax-coated tablet at a weight gain of about 1-30%, about 3-25%, or about 3-20%. In some embodiments, the solid suspension may be a 10-30% solid suspension, a 15-25% solid suspension, or a 15-20% solid suspension of the film coating. In some embodiments, the amount of film coating of the pharmaceutical composition (including all coatings) is at least about 1% by weight, at least 2% by weight, at least about 3% by weight, at least about 5% by weight, at least about 8% by weight, at least about 10% by weight, or at least about 12% by weight. In some embodiments, the amount of film coating of the pharmaceutical composition (including all coatings) is up to about 25% by weight, up to about 20% by weight, up to about 15% by weight, up to about 10% by weight, up to about 8% by weight, up to about 5% by weight, or up to about 3% by weight.

[0045] After the tablet is coated with a film coating, the film coating layer can be coated with an enteric coating, such as ACRYL-EZE® enteric coating. The enteric coating can include acrylic acid and / or acrylates. The enteric coating formulation can be sprayed onto a rotating or fluidized tablet bed. The drying conditions of the enteric coating process can remove the solvent, leaving a thin layer of coating material around the wax and film coated tablet.

[0046] In some embodiments, the enteric coating may be prepared as a solid suspension and applied to the wax and film coated tablets at a weight gain of about 20-50%, about 25-45%, or about 30-40%. In some embodiments, the solid suspension may be a 10-30% solid suspension, a 15-25% solid suspension, or a 15-20% solid suspension of the enteric coating. In some embodiments, the amount of enteric coating of the pharmaceutical composition (including all coatings) is at least about 10% by weight, at least about 15% by weight, at least about 20% by weight, or at least about 25% by weight. In some embodiments, the amount of enteric coating of the pharmaceutical composition (including all coatings) is up to about 50% by weight, up to about 45% by weight, up to about 40% by weight, up to about 35% by weight, or up to about 30% by weight.

[0047] The protective wax coating described herein can be used for many moisture sensitive APIs, or for highly soluble fast dissolving effervescent tablets. The wax coating can be applied to the tablet prior to application of the aqueous film coat to provide this protective wax coating layer. EXAMPLES

[0048] Example 1: AKST-4290 as an API. Alkahest compound AKST-2490 is a highly soluble API that can degrade in moisture. Applicant has been able to prevent degradation using the wax coating process described herein. This technique reduced coating time, limited water uptake in the core tablet, and improved the purity profile at T-0.

[0049] Specifically, wax was applied as a subcoat to the core tablets. In the case of AKST-4290, one of the purposes of this wax coat was to protect the API in the tablet from moisture. This API is highly hygroscopic and undergoes both physical and chemical changes when exposed to relative humidity above 40% (even for a few minutes). Relative humidity can be controlled during the upstream process of tablet making, which cannot be achieved with the aqueous coating process.

[0050] In this example, the film coating applied was OPADRY AMBII series, which is formulated to provide an oxygen and moisture barrier. However, since the film coating formulation is applied as a 15% solids aqueous solution, the core tablet is exposed to moisture during film coating. However, applicants have discovered that a thin layer of wax may be sufficient to protect the core tablet during film coating. Below is the composition of the tablet, the first wax coating, and the second film coating.

[0051] [Table 1]

[0052] The addition of 0.5% wax corresponds to a 0.5% weight gain of the core tablet. The addition of 3.0% OPADRY® coating corresponds to a 3% weight gain of the wax coated tablet.

[0053] The wax coating process was as follows: After the tablets were sufficiently heated, the intake and exhaust were turned off, wax paper was placed under the pan, and the carnauba wax was added slowly (over approximately 2-5 minutes) to the pan and spread over the top of the core tablets as the pan rotated. The carnauba wax was collected from the wax paper and spread over the top of the core tablets. The pan speed was adjusted based on visual observation of the tablet bed. The tablets were rolled with the wax for 5-10 minutes at approximately 3 RPM. After 5-10 minutes, the exhaust was turned on and run for an additional 3-5 minutes. The intake was turned on and run for an additional 3-5 minutes. The tablets could then be removed, ensuring that the exhaust temperature reached 46°C (± 2°C) before proceeding to film coating.

[0054] As shown in the table below, preliminary results indicate that wax and OPADRY® AMBII coated tablets have lower water content (measured by Karl Fischer analysis) than those coated with OPADRY® alone.

[0055] [Table 2]

[0056] Example 2: ALXN-1840 as an API. As shown in the table below, the ALXN-1840 tablet compound has a high level of sodium bicarbonate in the formulation to stabilize the API, which is a chelating agent and is highly reactive. During initial attempts to coat this compound, the tablets began to disintegrate in the coating pan during the coating process. Applicants were able to successfully apply a film coating to the tablets after applying a wax coating to the tablets.

[0057] After the tablets were fully heated, the exhaust was turned off and the carnauba wax was slowly added to the pan (over approximately 3-5 minutes) and distributed on top of the core tablets by the rotation of the pan. The tablets were rolled with the wax at approximately 3 RPM for 5-10 minutes. The pan speed was adjusted based on visual observation of the tablet bed. After 5-10 minutes, the exhaust was turned on and run for an additional 5-7 minutes. The tablets could then be removed for film coating. OPADRY® 200 Clear 203 A190001 was prepared as a 20% solids suspension and applied to the target tablets at a 20% weight gain. Next, Acryl-EZE White was prepared as a 20% solids suspension and applied to the film-coated and wax-coated tablets at a 35% weight gain. Below are the compositions of the tablets, first wax coating and second film coating.

[0058] [Table 3]

[0059] Figures 1A-1B illustrate mini-tablets subcoated without wax addition. Specifically, these photographs illustrate the results of coating mini-tablets without wax. As can be seen in the photographs, the mini-tablets were activated by the addition of water from the coating process. Activation of the mini-tablet core results in the mini-tablet core erupting from the coating shell during the coating process.

[0060] Figures 2A-2B illustrate uncoated core minitablets and enteric coated minitablets of Example 2 where 1% wax addition was applied prior to the film and enteric coating. Specifically, the photographs illustrate uncoated core minitablets (red) prior to wax addition and fully coated white minitablets. The wax application prior to the film and enteric coating prevented the minitablets from foaming during the coating process. Thus, Applicant has discovered that the wax coating can provide initial protection from moisture, thereby preventing the minitablets from activating during the initial application of the moisture barrier film coating.

[0061] Further definitions Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In some cases, terms having commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from what is commonly understood in the art.

[0062] Reference herein to "about" a value or parameter includes (and describes) a variation directed to the value or parameter itself. For example, a statement of "about X" includes a statement of "X." Additionally, the phrases "less than," "greater than," "up to," "at least," "less than or equal to," "greater than or equal to," or other similar phrases following a series of values ​​or parameters are intended to apply the phrase to each value or parameter in the series. For example, a statement that a layer has a thickness of at least about 5 cm, at least about 10 cm, or at least about 15 cm is intended to mean that the layer has a thickness of at least about 5 cm, at least about 10 cm, or at least about 15 cm.

[0063] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and / or," as used herein, refers to and encompasses any and all possible combinations of one or more of the associated listed items. It should further be understood that the terms "includes," "including," "comprises," and / or "comprising," as used herein, specify the presence of stated features, integers, steps, operations, elements, components, units, and / or groups thereof, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, units, and / or groups thereof.

[0064] This application discloses several numerical ranges in the text and figures. Since the disclosure can be implemented over the disclosed numerical ranges, even if the exact range limits are not stated literally in this specification, the disclosed numerical ranges inherently support any range or value within the disclosed numerical ranges, including the endpoints.

[0065] The above is presented to enable any person skilled in the art to make and use the disclosure, and is provided in the context of a particular application and its requirements. Various modifications to the preferred embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the disclosure. Thus, the disclosure is not intended to be limited to the embodiments shown, but is intended to be accorded the widest scope consistent with the principles and features disclosed herein.

Claims

1. A tablet comprising an active pharmaceutical ingredient (API), a first coating on the surface of the tablet comprising wax, and a second coating on the surface of the first coating comprising polyvinyl alcohol comprising a pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, comprising 0.5 to 1.0% w / w of wax.

3. The pharmaceutical composition according to claim 1 or 2, wherein the second coating is an OPADRY® moisture barrier film coating.

4. The pharmaceutical composition according to any one of claims 1 to 3, further comprising a third coating on the surface of the second coating, the third coating comprising acrylic acid and / or acrylate.

5. The pharmaceutical composition according to claim 4, wherein the third coating is an ACRYL-EZE® enteric coating.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the tablet comprises sodium bicarbonate.

7. A method for preparing a pharmaceutical composition, comprising: compressing a tablet comprising an active pharmaceutical ingredient (API); coating the surface of the tablet with a first coating comprising wax; coating the surface of the first coating with a second coating comprising polyvinyl alcohol comprising a method.

8. The method according to claim 7, wherein the step of coating the surface of the tablet with the first coating comprises coating the surface of the tablet such that the mass increase of the tablet from the first coating is 0.5 to 1.0%.

9. The method according to claim 7 or 8, wherein the step of coating the surface of the first coating comprises coating the surface of the first coating such that the mass increase of the tablet and the first coating from the second coating is 1 to 30%.

10. The method according to claim 9, wherein the mass increase of the tablet and the first coating from the second coating is 15 to 25%.

11. The method according to any one of claims 7 to 10, wherein the second coating is an OPADRY® moisture barrier film coating.

12. The method according to any one of claims 7 to 11, further comprising coating the surface of the second coating with a third coating comprising acrylic acid and / or acrylate.

13. The method according to claim 12, wherein the third coating is an ACRYL-EZE® enteric coating. **Claim 14** The method according to any one of claims 7 to 13, wherein the tablet contains sodium bicarbonate.

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