WO2021011538A1 - Formes galéniques capsules, leurs procédés de préparation et leurs procédés d'utilisation - Google Patents

Formes galéniques capsules, leurs procédés de préparation et leurs procédés d'utilisation Download PDF

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Publication number
WO2021011538A1
WO2021011538A1 PCT/US2020/041930 US2020041930W WO2021011538A1 WO 2021011538 A1 WO2021011538 A1 WO 2021011538A1 US 2020041930 W US2020041930 W US 2020041930W WO 2021011538 A1 WO2021011538 A1 WO 2021011538A1
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WIPO (PCT)
Prior art keywords
dosage form
cps
acid
amount
shell composition
Prior art date
Application number
PCT/US2020/041930
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English (en)
Inventor
Humera Ahmad
Ram GULLAPALI
Jing Lin
Original Assignee
R.P. Scherer Technologies, Llc
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Publication date
Application filed by R.P. Scherer Technologies, Llc filed Critical R.P. Scherer Technologies, Llc
Publication of WO2021011538A1 publication Critical patent/WO2021011538A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin

Definitions

  • the disclosure relates to capsule dosage forms containing, for example, a moisture sensitive pharmaceutical active (e.g., a salicylic acid, proton pump inhibitor and/or calcium channel blocker) that prevents migration of the pharmaceutical active ingredient into the shell and/or migration of water into the fill composition. Also disclosed are methods of preparation of such dosage forms and methods of use thereof.
  • a moisture sensitive pharmaceutical active e.g., a salicylic acid, proton pump inhibitor and/or calcium channel blocker
  • Capsule dosage forms are commonly used for oral administration of a variety of pharmaceuticals.
  • the capsules can be, for example, soft gelatin shell or hard shell (animal or vegetable variety).
  • Softgel capsules provide numerous advantages including: 1) fast dissolution, 2) taste-masking, 3) ease of swallowing, 4) fewer excipients as compared to tablets, 5) delivery of a liquid matrix that solubilizes and improves oral bioavailability of a marginally hydrophilic compound, 6) delivery of low and ultra-low doses of a compound, 7) delivery of low melting temperature compounds and 8) minimization of dust generation during manufacturing and thus, improved safety for production personnel.
  • certain active pharmaceutical compounds can migrate into the capsule shell and conversely, materials in the shell, such as moisture (e.g., water), can migrate into the fill composition, both of which can result in a lack of stability for moisture sensitive active pharmaceutical ingredients.
  • moisture e.g., water
  • the commercial production of all soft gelatin capsules include water, which cannot be completely removed without causing insufficient plasticity in the shell.
  • Some compounds are sensitive to the presence of even moderate amounts of moisture/water.
  • the residual water initially present in the capsule shell, can at least partly diffuse into the fill composition that contains the compound.
  • moisture from the atmosphere may also diffuse through the capsule shell into the fill.
  • the drug within the fill composition can migrate into the shell.
  • a shelf storage period of a few weeks or months to a few years is desirable for most drug products, and regulatory agencies need a demonstration of drug stability within the required shelf life, before approval is given to market the drug product.
  • This requirement includes the maintenance of an adequate amount of drug activity in the product within the required shelf-life when the product package is stored at a specified humidity and temperature in accordance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for stability.
  • ICH International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use
  • Aspirin also known as acetylsalicylic acid
  • Aspirin is one of the most widely administered moisture sensitive drugs.
  • the aspirin may be dissolved in a lipophilic fluid, an oily solvent or a
  • the monoglyceride fill optionally containing other excipients to stabilize the aspirin against hydrolysis caused by the presence of moisture.
  • the shell may also be modified to contain, for example, cyclodextrin to increase stability.
  • a dosage form comprising: a fill composition comprising: at least one moisture sensitive pharmaceutical active (e.g., at least one of a salicylic acid, a proton pump inhibitor, a calcium channel blocker, salts thereof, esters thereof, solvates thereof or combinations thereof); and a carrier; and a shell
  • composition wherein the fill composition is enclosed within the shell composition.
  • a method of treating pain comprising: administering to a patient in need thereof a dosage form according to
  • a method of reducing fever comprising: administering to a patient in need thereof a dosage form according to
  • a method of reducing or prevent blood clots comprising: administering to a patient in need thereof a dosage form according to embodiments herein.
  • a method of treating arthritis comprising: administering to a patient in need thereof a dosage form according to embodiments herein.
  • a method of treating at least one of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, symptomatic endoscopy negative reflux disease, laryngopharyngeal reflux causing laryngitis, chronic cough, Barrett’s esophagus, eosinophilic esophagitis, stress gastritis, ulcers and gastrinomas comprising: administering to a patient in need thereof a dosage form according to embodiments herein.
  • a method of reducing stomach acid production comprising: administering to a patient in need thereof a dosage form according to embodiments herein.
  • a method of treating at least one of heart disease, hypertension, high blood pressure, coronary artery disease, coronary spasm, angina, abnormal heart rhythm, hypertrophic cardiomyopathy, diastolic heart failure and Raynaud’s syndrome comprising: administering to a patient in need thereof a dosage form according to embodiments herein.
  • a method of preparing a dosage form comprising: preparing a fill composition, comprising combining at least one moisture sensitive pharmaceutical active (e.g., at least one of a salicylic acid, a proton pump inhibitor, a calcium channel blocker, salts thereof, esters thereof, solvates thereof and combinations thereof) with a carrier; and enclosing the fill composition within a shell composition.
  • at least one moisture sensitive pharmaceutical active e.g., at least one of a salicylic acid, a proton pump inhibitor, a calcium channel blocker, salts thereof, esters thereof, solvates thereof and combinations thereof
  • PPI proton pump inhibitor
  • the term“about” in connection with a measured quantity refers to the normal variations in that measured quantity as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment.
  • the term“about” includes the recited number ⁇ 10%, such that“about 10” would include from 9 to 11.
  • the term“at least about” in connection with a measured quantity refers to the normal variations in the measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and precisions of the measuring equipment and any quantities higher than that.
  • the term“at least about” includes the recited number minus 10% and any quantity that is higher such that“at least about 10” would include 9 and anything greater than 9. This term can also be expressed as“about 10 or more.”
  • the term“less than about” typically includes the recited number plus 10% and any quantity that is lower such that“less than about 10” would include 11 and anything less than 11. This term can also be expressed as“about 10 or less.”
  • pharmaceutical means any compound, substance, drug, prodrug, medicament, or active ingredient having a therapeutic or pharmacological effect, and which is suitable for administration to a human or animal, in a composition that is particularly suitable for oral administration.
  • the pharmaceuticals of the invention include base drugs as well as any of their salts, esters, solvates, etc. that are useful for delivering the pharmaceutical activity of the compositions.
  • dietary supplement refers to a dietary ingredient intended to supplement the diet.
  • the dietary supplement may include: vitamins, minerals, herbs or other botanicals, amino acids, and/or substances such as enzymes, organ tissues, glandulars and/or metabolites.
  • the term“shell” as used herein means the outer component of a capsule dosage form.
  • the shell may be in the form of a softgel, a hard shell, both as animal or vegetable origin.
  • soft gelatin capsule or“softgel” as used herein means a capsule formed predominantly of gelatin (i.e., animal or vegetable origin), glycerin, sorbitol and water.
  • hard shell as used herein means a two-piece outer component having a cap-piece that slips over the open end of a body-piece.
  • Hard shells are typically formed of gelatin or hydroxypropyl methylcellulose and other materials suitable for a liquid fill composition.
  • the term“vegetarian shell” as used herein means the outer component of a capsule dosage form that is typically formed of a vegetarian material such as a cellulose polymer (e.g., hypromellose) or a polysaccharide polymer (e.g., pullulan).
  • a vegetarian material such as a cellulose polymer (e.g., hypromellose) or a polysaccharide polymer (e.g., pullulan).
  • a salicylic acid or“salicylic acids” as used herein means a class of acids including the chemical compound known as salicylic acid, which is a type of phenolic acid and beta hydroxy acid.
  • moisture sensitive means that the fill composition and/or shell composition are subject to undesirable changes in the presence of water/moisture. Such undesirable changes include hydrolysis or oxidation of the pharmaceutical or excipient, reactions with other components in the fill composition or the shell composition, degradation of the pharmaceutical active or excipient, or changes in physical characteristics of the pharmaceutical active or excipient.
  • Moisture sensitivity of the pharmaceutical active or excipient can be evidenced by a rate of formation of a particular degradation product or products over a period of time at a particular temperature and humidity. The period of time can be based on the required shelf life of the pharmaceutical, as is typically required by a regulatory agency (e.g., the U.S.
  • dosage forms containing a fill composition having a moisture sensitive pharmaceutical active, for example, at least one of a salicylic acid, a proton pump inhibitor, a calcium channel blocker, salts thereof, esters thereof, solvates thereof and/or combinations thereof, and a carrier; and a shell composition, where the fill composition is enclosed within the shell composition.
  • a moisture sensitive pharmaceutical active for example, at least one of a salicylic acid, a proton pump inhibitor, a calcium channel blocker, salts thereof, esters thereof, solvates thereof and/or combinations thereof, and a carrier
  • a shell composition where the fill composition is enclosed within the shell composition.
  • a viscosity of the fill composition is less than about 5,000 cps, or less than about 4,000 cps, or less than about 3,000 cps, or less than about 2,000 cps, or less than about 1,000 cps, or less than about 900 cps, or less than about 800 cps, or less than about 700, cps, or less than about 600 cps as measured by USP41-NG36 chapter (1911), Rheometry at room temperature and atmospheric pressure. If the viscosity of the fill composition is too high, it is difficult to encapsulate the fill composition and may reduce drug release during dissolution. If the viscosity is too low, the fill composition cannot suspend the drug material causing the drug powder to sediment, which may affect uniformity of the active ingredient in the fill and also the dissolution.
  • the moisture sensitive pharmaceutical active for example, at least one of a salicylic acid, proton pump inhibitor (PPI), calcium channel blocker, salts thereof, esters thereof, solvates thereof and/or combinations thereof (e.g., acetylsalicylic acid), is in the form of at least one of a powder, granules and/or pellets having a size of about 1 pm to about 250 pm, or about 5 pm to about 180 pm, or about 10 pm to about 150 pm, or a particle size distribution of less than about 250 pm, or less than about 180 pm, or less than about 160 pm, or less than about 150 pm, or less than about 140 pm, or less than about 100 pm.
  • a salicylic acid for example, at least one of a salicylic acid, proton pump inhibitor (PPI), calcium channel blocker, salts thereof, esters thereof, solvates thereof and/or combinations thereof (e.g., acetylsalicylic acid)
  • PPI proton pump inhibitor
  • calcium channel blocker salts thereof
  • the moisture sensitive pharmaceutical active is suspended in the carrier.
  • the suspension of the pharmaceutical active in the carrier may be uniform or approximately uniform.
  • the uniformity of the suspension can be determined by measuring the viscosity of the suspension (using USP method (1911), Rheometry) within about 10 minutes after formation and comparing to the viscosity of the suspension measured at least about 2 hours later. If the two viscosity measurements are within about ⁇ 10% of each other, the suspension is approximately uniform, if they are the same (i.e., no detectable settling of the pharmaceutical active), then the suspension is uniform.
  • the moisture sensitive pharmaceutical active ingredients can include a salicylic acid.
  • Suitable salicylic acids include, but are not limited to, acetylsalicylic acid, salicylic acid, bismuth subsalicylic acid, choline salicylic acid, diflunisal, magnesium salicylic acid, salsalate, salts thereof, esters thereof, solvates thereof and/or combinations thereof.
  • the dosage form contains acetylsalicylic acid.
  • the salicylic acid (e.g., acetylsalicylic acid) can be in an amount of about 50 mg to about 650 mg, or about 75 mg to about 500 mg, or about 80 mg to about 400 mg, or about 100 mg to about 325 mg, or about 75 mg, or about 81 mg, or about 100 mg, or about 300 mg, or about 325 mg, or about 500 mg, or about 650 mg.
  • the moisture sensitive pharmaceutical active is acetylsalicylic acid (i.e., aspirin).
  • the amount of aspirin in the dosage form can be a dosage approved by a regulatory agency. For example, in the United States, aspirin dosages range from about 70 mg to about 500 mg. Aspirin is approved for a dose of 75 mg, 100 mg, 300, mg or 500 mg in England and for a dose of 325 mg or 500 mg in the United States. Smaller dosages of aspirin, such as 75 mg or 81mg, are also approved in the United States. A dosage of 500 or 650 mg aspirin may be used for treatment of some diseases.
  • the moisture sensitive pharmaceutical active can include a proton pump inhibitor (PPI).
  • PPIs include, but are not limited to, omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, dexlansoprazole, salts thereof, esters thereof, solvates thereof and/or combinations thereof.
  • the proton pump inhibitor can be in an amount of about 10 mg to about 400 mg, or about 60 mg to about 350 mg, or about 75 mg to about 325 mg, or about 81 mg or about 325 mg.
  • the dosage form may contain esomeprazole in an amount of about 0.1 wt. % to about 30 wt. % of the fill composition.
  • the moisture sensitive pharmaceutical active can include a calcium channel blocker.
  • Suitable calcium channel blockers include, but are not limited to, a dihydropyridine, for example, at least one of amlodipine, felodipine, fesoterodine, isradipine, nifedipine, nimodipine and/or nisoldipinenicardipine.
  • the calcium channel blocker can be in an amount of about 5 mg to about 240 mg, or about 10 to about 120 mg, or about 30 to about 60 mg, or about 10 mg, or about 20 mg, or about 30 mg, or about 60 mg, or about 120 mg.
  • the carrier can include, but is not limited to, an anti foaming agent, surfactant, diluent, binder, lubricant, disintegrant, filler, coloring agent, wetting or emulsifying agent, pH buffering agent, oil, solubilizer and/or preservative.
  • Suitable anti-foaming agents include, but are not limited to, simethicone, dimethicone, silicone oil, polydimethylsiloxane, mineral oil, vegetable oil, castor oil, paraffin oil, fatty acid, fatty alcohol, fatty acid ester, a polyacrylate, mono-glyceride, di-glyceride, wax, paraffin wax and/or polypropylene glycol.
  • the carrier contains simethicone, alone or in combination with other anti-foaming agents and/or other excipients as listed above.
  • an anti foaming agent such as simethicone, for example, having a particular viscosity range suspends the moisture sensitive pharmaceutical active (e.g., aspirin) as a carrier, which provides unexpected stability and unexpectedly reduces or eliminates moisture migration from the shell into the fill or drug migration from the fill into the shell.
  • the carrier contains simethicone. Simethicone can be a viscous liquid and is a mixture of polydimethylsiloxane and silicon dioxide.
  • Simethicone can function as a surface- active agent and defoamer and/or dispersant of gas bubbles. Simethicone can change the surface tension of the bubbles in a solution enabling the bubbles to coalesce. Simethicone is not absorbed in the stomach, so in the present dosage forms simethicone can be a diluent or suspending agent for the moisture sensitive pharmaceutical active and also has the characteristic of being an anti-flatulent. Simethicone is considered inert and does not interact or degrade the pharmaceutical active ingredient.
  • the simethicone can have a viscosity of about 1 cps to about 1,000 cps or about 50 cps to about 750 cps, or about 100 cps to about 600 cps, or about 570 cps as measured by USP41-NF36 chapter (1911), Rheometry at room temperature (e.g., 20 °C) and atmospheric pressure.
  • the at least one anti-foaming agent e.g., simethicone
  • a weight ratio of the at least one anti-foaming agent (e.g., simethicone) to the at least one of a salicylic acid, proton pump inhibitor, calcium channel blocker, salts thereof, esters thereof, solvates thereof and/or combinations thereof (e.g., acetylsalicylic acid) is about 1 :20 to about 20: 1, or 1 : 15 to about 15: 1, or about 1 : 10 to about 10: 1, or about 1 :5 to about 5: 1, or about 1:3 to about 3: 1, or about 2:3.
  • a weight ratio of the at least one anti-foaming agent e.g., simethicone
  • a salicylic acid, proton pump inhibitor, calcium channel blocker, salts thereof, esters thereof, solvates thereof and/or combinations thereof e.g., acetylsalicylic acid
  • the carrier includes simethicone and a weight ratio of the simethicone to the at least one of a salicylic acid, proton pump inhibitor, calcium channel blocker, salts thereof, esters thereof, solvates thereof and/or combinations thereof (e.g., acetylsalicylic acid) is about 2:3.
  • the dosage form contains a fill composition consisting essentially of acetylsalicylic acid and simethicone at a weight ratio of the simethicone to the acetylsalicylic acid of about 2:3.
  • the fill composition contains a carrier comprising simethicone at a viscosity of about 1 cps to about 1,000 cps, or about 50 cps to about 750 cps, or about 100 cps to about 600 cps, or about 570 cps as measured by USP41-NF36 chapter (1911), rheometry.
  • Suitable surfactants for the pharmaceutical active carrier include, but are not limited to, a non-ionic surfactant, lipophilic surfactant, hydrophilic surfactant, Polysorbate ® 80, Polysorbate 85, lecithin, polyoxyethylene, polyoxyethylene-20 cetyl ether, polyoxyethylene- 20 stearate, polyoxypropylene-15 stearyl ether, sucrose palmitate stearate, octyl-b-O- glucopyranoside, sodium lauryl sulphate, sorbitan-monostearate esters, glycerol di-ester, lecithin, amino propionic acid, dimethyl sulfoxide (DMSO) and/or mixtures thereof.
  • DMSO dimethyl sulfoxide
  • Suitable hydrophilic surfactants include, but are not limited to, polyethylene glycol (PEG) fatty acid esters, PEG ethers, PEG glycerides, such as PEG 35 Castor oil, PEG 40, hydrogenated castor oil and/or saturated polyglycolyzed glycerides.
  • PEG polyethylene glycol
  • Suitable non-ionic surfactants may have a Hydrophile-Lipophile Balance (HLB) value of less than 8, for example, macrogolglycerides, sorbitan esters and mono- and diglycerides, glycol mono and diesters, glyceryl esters, PEG esters, such as linoleoyl macrogolglycerides, oleoyl macrogolglycerides, propylene glycol laurate, glyceryl mono-oleate, Span ® 80, and/or medium chain mono- and/or di-glycerides.
  • HLB Hydrophile-Lipophile Balance
  • the surfactant can at least one of sodium lauryl sulphate in an amount of about 0.01 wt.% to about 10 wt %, sorbitan-monostearate esters in an amount of about 0.01 wt.% to about 10 wt.%, glycerol di-ester in an amount of about 0.01 wt.% to about 10 wt.%, lecithin in an amount of about 0.01 wt.% to about 10 wt.%, amino propionic acid in an amount of about 0.01 wt.% to about 10 wt.%, dimethyl sulfoxide (DMSO) in an amount of about 0.01 wt.% to about 10 wt.%, and in combinations thereof.
  • the carrier comprises a combination of Polysorbate 80 and lecithin alone or in combination.
  • the HLB value of a surfactant is a guide used for pharmaceutical active formulations.
  • the HLB values may not accurately reflect the true physical and/or chemical nature of the compounds.
  • commercial surfactant products are generally not pure compounds, but are often complex mixtures of compounds.
  • the HLB value reported for a particular compound may more accurately be characteristic of the commercial product of which the compound is a major component.
  • Different commercial products having the same primary surfactant compound can, and typically do, have different HLB values depending on the exact mixtures.
  • HLB values as a guide, a person skilled in the art can still readily identify surfactants having suitable hydrophilicity or hydrophobicity for use in the dosage forms as described herein.
  • the surfactant in the fill composition may facilitate improved dissolution of the pharmaceutical active and/or excipient in the digestive tract of a patient, which is an aqueous environment.
  • the surfactant is capable of helping diffuse or solubilize the pharmaceutical active and/or excipient from the oil-based fill into the aqueous environment of the digestive tract.
  • the solubilized pharmaceutical active and/or dietary supplement can then be absorbed by the digestive tract.
  • the surfactant in the fill composition may be in an amount of about 0.01 wt. % to about 10 wt. %, or from about 0.05 wt. % to about 9 wt. %, or from about 0.1 wt. % to about 9 wt. %, or from about 0.2 wt. % to about 8.5 wt. %, or from about 0.3 wt. % to about 8.5 wt. %, or from about 0.4 wt. % to about 8 wt. %, or from about 0.5 wt. % to about 7.5 wt. %, or from about 0.6 wt. % to about 7.5 wt.
  • wt. % or from about 0.7 wt.% to about 7 wt. %, or from about 0.8 wt. % to about 7 wt. %, or from about 0.9 wt. % to about 6.5 wt. %, or from about 1 wt. % to about 6 wt. %, or from about 1.5 wt. % to about 6 wt. %, or from about 2 wt. % to about 5.5 wt. %, or from about 2.5 wt. % to about 5 wt. %, or from about 3 wt. % to about 5 wt. %, or from about 3.5 wt. % to about 5 wt. %, or from about 4 wt. % to about 5 wt. % based on the total weight of the fill composition.
  • Suitable diluents for the carrier include, but are not limited to, lactose, lactose monohydrate, starch, mannitol, sorbitol, dextrose monohydrate, microcrystalline cellulose, dibasic calcium phosphate dihydrate, sucrose-based diluents, confectioner’s sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate granular, dextrates, dextrose, inositol, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, bentonite, polyvinylpyrrolidone and/or combinations thereof.
  • Suitable binders for the carrier include, but are not limited to, a cellulosic polymer, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, sodium carboxymethylcellulose, a polyethylene glycol, an acrylic polymer, an acrylic copolymer, a graft copolymer of polyvinyl alcohol and polyethylene glycol, a polyvinyl alcohol, alginic acid, sodium alginate, starch, pregelatinized starch, sucrose, guar gum, a fatty alcohol, lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, a fatty acid, a fatty acid ester, a fatty acid glyceride, a monoglyceride, a diglyceride, a triglyceride, a hydrogenated fat, a hydrocarbon, stearic acid, hydrophobic material, a hydrophilic
  • Suitable lubricants for the carrier include, but are not limited to, magnesium stearate, talc, silica, fumed silica, colloidal silica, calcium stearate, carnauba wax, long chain fatty alcohols, a wax, stearic acid, stearyl alcohol, mineral oil, paraffin, micro crystalline cellulose, glycerin, propylene glycol and/or polyethylene glycol.
  • Suitable disintegrants for the carrier include, but are not limited to, sodium starch glycolate, a clay, a cellulose, methylcellulose, sodium carboxymethyl cellulose,
  • carboxymethylcellulose cross-linked sodium carboxymethylcellulose, starch, cross-linked polyvinylpyrrolidone, an alginate, a cornstarch, a pre-gel atinized com starches, a gum, agar gum, guar gum, locust bean gum, pectin, tragacanth and/or mixtures thereof.
  • Suitable fillers for the carrier include, but are not limited to, glycerol, sorbitol, vegetable or other oils and/or mixtures thereof.
  • Suitable coloring agents for the carrier include, but are not limited to, an azo dye, quinophthalone dye, triphenylmethane dye, xanthene dye, iron oxide, iron hydroxide, titanium dioxide, sunset yellow, allura red, amaranth, koki neil red, azogeranin, tartrazine, brilliant black, canthaxanthin, patent blue, fast green, brilliant blue, acid green, erythrosine, quinoline yellow, indigotin, curcumin, carbon black and/or mixtures thereof.
  • Suitable wetting or emulsifying agents for the carrier include, but are not limited to, sodium lauryl sulphate, polyoxyethylene sorbitan mono-oleate, a polysaccharide, a glycerol esters, a cellulose ether, a sorbitan ester, a polysorbate, naturally occurring materials thereof, semi synthetic derivatives thereof and/or mixtures thereof.
  • Suitable pH buffering agents for the carrier include, but are not limited to, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate, di sodium phosphate and/or mixtures thereof.
  • Suitable oils for the carrier can include, but are not limited to, almond oil, grape seed oil, olive oil, soybean oil (or soybean oil), coconut oil (refined), vegetable oil, palm oil, GeloilTM SC oil and/or hydrogenated vegetable oil.
  • the oil can be in an amount of up to about 30 wt. %, or up to about 25 wt. %, or up to about 20 wt. %, or up to about 15 wt. %, or up to about 10 wt. %, based on the total weight of the liquid fill.
  • a suitable oil can be at least one of almond oil in an amount of about 0.5 wt.% to about 80 wt.%, grape seed oil in an amount of about 0.5 wt.% to about 80 wt.%, olive oil in an amount of about 0.5 wt.% to about 80 wt.%, soya oil in an amount of about 0.5 wt.% to about 80 wt.%, coconut oil (refined) in an amount of about 0.5 wt.% to about 80 wt.%, vegetable oil in an amount of about 0.5 wt.% to about 80 wt.% and/or combinations thereof.
  • the oil comprises a combination of coconut oil, almond oil and/or grape seed oil.
  • one or more of the oils may be refined.
  • the oil is a blend of hydrogenated soybean oil, glyceryl di stearate, and polyglyceryl-3 dioleate, alone or in combination with coconut oil and/or lauric acid.
  • Such oil may be used alone or in combination with other oils such as coconut oil or with lauric acid and has the advantage of being water dispersible and is easy to process since the fill preparation does not require heating when used.
  • Suitable preservatives for the carrier include, but are not limited to, phenol, alkyl esters of parahydroxybenzoic acid, o-phenylphenol benzoic acid, boric acid, sorbic acid, chlorobutanol, benzyl alcohol, thimerosal, phenyl mercuric acetate, phenyl mercury nitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride, methyl paraben, propyl paraben, salts thereof and/or mixtures thereof.
  • the dosage form may further include a dietary supplement, vitamin and/or antioxidant.
  • Suitable dietary supplements, vitamins and/or antioxidants for the dosage form include, but are not limited to, ascorbic acid, a-tocopherol (vitamin E), vitamin E-succinate, vitamin E-palmitate, butylhydroxyanisol, butylhydroxytoluene, ascorbylic palmitate, monothio-glycerine, coniferyl benzoate, nordihydroguaiaretic acid, a gallic acid ester, phosphoric acid, sodium bisulphite, butylhydroxytoluene (BHT), butylhydroxyanisol (BHA), a-tocopherol, probiotics, SAM-e, salts thereof, derivatives thereof and/or mixtures thereof.
  • probiotics may be in an amount of about 1.0 to about 50 wt. % of the fill composition
  • SAMe may be in an amount of about 10 wt. % to about 60 wt. % of the fill composition
  • the vitamins may be in an amount of about 0.1 wt. % to about 60 wt. % of the fill composition, with all weight percentages being based on the total weight of the fill composition.
  • moisture sensitive dietary supplements include, but are not limited to, probiotics, some vitamins such as ascorbic acid, vitamin Bl, B12, calcium pantothenate and/or folic acid.
  • other actives that may be stable in the fill formulations used for Aspirin include, but are not limited to, probiotics in an amount of about 1.0 wt.% to about 50 wt.% of the fill composition, levothyroxine in an amount of about 0.1 wt.% to about 30 wt.% of the fill composition, esomprazole in an amount of about 0.1 wt.% to about 30 wt.%, sodium valproate in an amount of about 0.1 wt.% to about 30 wt.% of the fill composition and/or combinations thereof.
  • probiotics in an amount of about 1.0 wt.% to about 50 wt.% of the fill composition
  • levothyroxine in an amount of about 0.1 wt.% to about 30 wt.% of the fill composition
  • esomprazole in an amount of about 0.1 wt.% to about 30 wt.%
  • sodium valproate in an amount of about 0.1 wt.%
  • the fill composition comprises aspirin in an amount of about 10 wt.% to about 50 wt.%, at least one surfactant in an amount of about 0.1 wt.% to about 10 wt.% and at least one oil in an amount of about 1 wt.% to about 80 wt.%.
  • the shell composition is in the form of at least one of a soft-shell or a hard shell (i.e., animal or vegetable origin).
  • the shell composition comprises gelatin.
  • the gelatin may be in an amount of about 15 wt.% to about 65 wt.%, or about 20 wt.% to about 60 wt.%, or about 25 wt.% to about 50 wt.%, or about 30 wt.% to about 45 wt.%, or about 30 wt.% to about 40 wt.% based on a total weight of the shell composition.
  • the gelatin is in an amount of about 50 mg to about 500 mg, or about 75 mg to about 400 mg, or about 100 mg to about 300 mg, or about 125 mg to about 200 mg, or about 150 mg.
  • the shell can include (e.g., in addition to the gelatin) at least one of a plasticizer, a coloring agent and/or a glidant.
  • Suitable plasticizers include, but are not limited to, glycerol, sorbitol, mixtures of sorbitol and sorbitan, propylene glycol, 1-2 propylene glycol, polyethylene glycol and/or macrogol 200 600
  • the plasticizer includes a combination of propylene glycol and glycerol.
  • the propylene glycol may be in an amount of about 0.0001 mg to about 0.01 mg, or about 0.000125 mg to about 0.0075 mg, or about 0.000175 mg to about 0.0050 mg, or about 0.0002 mg to about 0.0025 mg, or about 0.0002 mg.
  • the propylene glycol may be in an amount of about 0.000015 wt.% to about 0.0015 wt.%, or about 0.00011 wt.% based on a total weight of the shell composition.
  • the glycerol may be in an amount of about 1 mg to about 250 mg, or about 5 mg to about 225 mg, or about 10 mg, to about 200 mg, or about 25 mg to about 175 mg, or about 50 mg to about 150 mg, or about 51.6 mg, or about 75 mg, or about 100 mg.
  • the glycerol may be in an amount of about 10 wt.% to about 50 wt.%, or about 15 wt.% to about 40 wt.%, or about 20 wt.% to about 30 wt.%, or about 25 wt.%, or about 26 wt.%, or about 27 wt.%, or about 28 wt.%, or about 29 wt.%, or about 30 wt.%, or about 31 wt.% based on a total weight of the shell composition.
  • Suitable coloring agents for the shell composition include, but are not limited to, an azo dye, quinophthalone dye, triphenylmethane dye, xanthene dye, iron oxide, iron hydroxide, titanium dioxide, sunset yellow, allura red, amaranth, koki neil red, azogeranin, tartrazine, brilliant black, canthaxanthin, patent blue, fast green, brilliant blue, acid green, erythrosine, quinoline yellow, indigotin, curcumin, carbon black and/or mixtures thereof.
  • the coloring agent comprises titanium dioxide and/or sunset yellow.
  • the titanium dioxide may be in an amount of about 0.05 to about 1.0 mg, or about 0.075 to about 0.75 mg, or about 0.1 mg to about 0.5 mg, or about 0.1 mg to about 0.5 mg, or about 0.394 mg. In embodiments, the titanium dioxide may be in an amount of about 0.01 wt.% to about 1.0 wt.%, or about 0.05 wt.% to about 0.5 wt.%, or about 0.1 wt.% to about 0.3 wt.%, or about 0.22 wt.%, or about 0.23 wt.%, or about 0.24 wt.% based on a total weight of the shell composition.
  • the sunset yellow may be in an amount of about 0.05 to about 1.0 mg, or about 0.075 to about 0.75 mg, or about 0.1 mg to about 0.5 mg, or about 0.1 mg to about 0.5 mg, or about 0.174 mg. In embodiments, the sunset yellow may be in an amount of about 0.01 wt.% to about 0.15 wt.%, or about 0.02 wt.% to about 0.14 wt.%, or about 0.05 wt.% to about 0.1 wt.%, or about 0.08 wt.%, or about 0.09 wt.%, or about 0.099 wt.% or about 0.1 wt.% based on a total weight of the shell composition.
  • Suitable glidants for the shell composition include, but are not limited to, calcium phosphate, calcium silicate, powdered cellulose, magnesium silicate, magnesium trisilicate, silicon dioxide, talcum, colloidal silica, colloidal anhydrous silica and/or mixtures thereof.
  • the glidant comprises colloidal anhydrous silica.
  • the colloidal anhydrous silica may be in an amount of about 0.001 to about 0.1 mg, or about 0.00125 mg to about 0.075 mg, or about 0.0015 mg to about 0.05 mg, or about 0.00175 mg to about 0.025 mg, or about 0.01 mg to about 0.02 mg, or about 0.0197 mg.
  • the colloidal anhydrous silica may be in an amount of about 0.005 wt.% to about 0.05 wt.%, or about 0.006 wt.% to about 0.04 wt.%, or about 0.005 wt.% to about 0.03 wt.%, or about 0.006 wt.% to about 0.02 wt.%, or about 0.01 wt.% based on a total weight of the shell composition.
  • the shell composition contains water.
  • the water may be in an amount of about 1 mg to about 50 mg, or about 5 mg to about 40 mg, or about 10 mg to about 30 mg, or about 12 mg to about 20 mg, or about 13 mg, or about 14 mg, or about 15 mg.
  • the water may be in an amount of about 1 wt.% to about 15 wt.%, or about 5 wt.% to 10 wt.%, or about 6 wt.%, or about 7 wt.%, or about 8 wt.%, or about 9 wt.% based on a total weight of the shell composition.
  • the shell composition may be included in the shell composition, such as components for modulating capsule dissolution rate or improving the rheology of the composition during the manufacturing process.
  • components for modulating capsule dissolution rate or improving the rheology of the composition during the manufacturing process may be included in the capsule shell formation stage, some of the water in the composition is removed by drying under critically controlled conditions, but a quantity of water, for example, up to 5-8% of the total weight of the finished capsule remains, in the shell.
  • the shell composition can include a cyclodextrin.
  • the plasticizer may be a polyhydroxyl alcohol, such as glycerol, sorbitol, sorbitol/sorbitan mixtures, 1-2 propylene glycol, macrogol 200-600 and/or mixtures thereof.
  • the cyclodextrin can include, but is not limited to, b-cyclodextrin and hydroxypropyl-P- cyclodextrin.
  • the shell composition can have about 0.7 wt. % to about 20 wt. % of cyclodextrin, from about 20 wt. % to about 50 wt. % of gelatin, from about 1 wt.
  • the composition when the cyclodextrin is b-cyclodextrin, the composition includes about 0.1 wt. % to about 2.5 wt. % of b-cyclodextrin; when the cyclodextrin is hydroxypropyl-b- cyclodextrin, the composition can include about 1 wt. % to about 20 wt. % of hydroxypropyl- P-cyclodextrin.
  • a lubricant is used as a moisture barrier in the soft gelatin capsule.
  • the goal of using the lubricant is to form a hydrophobic layer of the lubricant between the shell and fill, which is immiscible with the fill.
  • the lubricant layer can minimize the migration of moisture from the shell into the fill.
  • the lubricant layer is preferably a solid membrane, though a solid membrane may be difficult to form and it may also be difficult to maintain its integrity as the shell shrinks significantly during drying.
  • a liquid membrane of the lubricant is more feasible in both the production step and for maintenance of the integrity of the membrane within the soft gelatin capsules during the storage of the capsules.
  • the lubricant has the normal function of lubricating the gel ribbon in an encapsulating machine, in addition to forming a moisture barrier.
  • the lubricant is required to be immiscible with both the shell and the fill, especially the oil component in the fill.
  • Such a lubricant will be able to form a layer of the lubricant between the shell and fill to prevent moisture migration from the shell to the fill during drying and storage of the soft gelatin capsules. Therefore, the choice of lubricant is can be predominately affected by, or even dependent on, the oil component in the fill.
  • the lubricant may be substantially immiscible or totally immiscible in the oil component.
  • the term“substantially immiscible” refers to a lubricant being able to form a stable separate phase (layer) from a substantially uniform mixture of the lubricant and the oil component at 1 : 1 volume ratio.
  • the lubricant in the separate phase comprises at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% of the lubricant used to produce the substantially uniform mixture.
  • the choice of the lubricant for forming the moisture barrier depends on the characteristics of the oil component in the fill.
  • a person skilled in the art can conduct routine tests for selecting a suitable lubricant that is substantially immiscible in the oil component used in the fill. Further, routine tests may be performed to ensure that the lubricant is not immiscible in the gel used in the encapsulation of the fill.
  • the lubricant may be a hydrophobic liquid with a low surface tension.
  • examples of such lubricants include dimethicone 350 (DM350) and isopropyl myristate (IPM).
  • DM350 dimethicone 350
  • IPM isopropyl myristate
  • the“350” denotes that the dimethicone has a viscosity of 350 cSt.
  • dimethicone with different viscosities may also be used, providing that such use is permitted for oral ingestion by regulatory agencies.
  • dimethicones with viscosities of 50 cSt, 100 cSt, 200 cSt, or even 500cSt may be used in some cases.
  • the lubricant is applied onto the surface of a gelatin gel ribbon (or net) to function as lubricant for the gel ribbon (or net). After encapsulation, the lubricant on the inner surface of the shell forms a layer separating the shell and fill material and functions as a moisture barrier.
  • DM350 and IPM are used together as the lubricant. This combination works well as IPM is a good solvent for DM350.
  • the lubricant layer on the inner surface of the shell can maintain its integrity during storage of the capsules.
  • the lubricant layer can have sufficient thickness to maintain the strength and physical integrity of the layer.
  • a water scavenger may be included in the carrier.
  • water scavenger refers to a substance that separates small amounts
  • Water scavengers useful in the fill composition include multivalent alkali metal oxides (MAMOs) that can scavenge small amounts of water present in the soft gelatin capsule. Another suitable water scavenger is copovidone. Other water scavengers include solid polyhydroxyl ated organic compounds and/or water-soluble hygroscopic salts including sugars, polysaccharides and/or polyols. Examples of polysaccharides are chondroitin sulphate, hyaluronic acid, guar gum, carrageenan, chitosan, alginate, agar and/or starch.
  • polyols examples include erythritol, sorbitol, inositol and/or polyvinyl alcohol.
  • water-soluble hygroscopic salts are calcium sulphate hemihydrate, which is capable of trapping one mole of water per mole of salt and/or anhydrous calcium chloride which is capable of trapping up to six moles of water per mole of salt.
  • Suitable solubilizers for the carrier include, but are not limited to, to Gel oilTM SC oil, alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, maltodextrins, cyclodextrins and/or derivatives thereof.
  • alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, manni
  • Solubilizers may also be ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG.
  • Solubilizers may also be amides, such as 2-pyrrolidone, 2-piperidone, F- caprolactam, N-alkyl pyrrolidone, N-hydroxyalkyl pyrrolidone, N-alkyl piperidone, N- alkyl caprolactam, dimethylacetamide, polyvinylpyrrolidone; esters, such as ethyl propionate, tributyl citrate, acetyl tri ethyl citrate, acetyl tributyl citrate, tri ethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, e-caprolactone and isomers thereof, d-valerolactone and isomers thereof, b- butyrolactone and isomers thereof.
  • Other solubilizers known in the art
  • Preferred solubilizers include ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, maltodextrins, cyclodextrins and derivatives thereof, ethyl propionate, tributyl citrate, acetyl tri ethyl citrate, acetyl tributyl citrate, tri ethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol diacetate, e-caprolactone and isomers thereof, g
  • More preferred solubilizers are ethanol, isopropanol, benzyl alcohol, ethylene glycol, propylene glycol, 1,3 -butanediol, glycerol, pentaerythritol, sorbitol, glycofurol, dimethyl isosorbide, polyethylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxypropylcyclodextrins, sulfobutyl ether derivatives of cyclodextrins, ethyl propionate, tributyl citrate, tri ethyl citrate, ethyl oleate, ethyl caprylate, triacetin, b-butyrolactone and isomers thereof, 2-pyrrolidone, N-methylpyrrolidone, N- ethylpyrrolidone, N-hydroxyethylpyrrol
  • Still more preferred solubilizers are triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, propylene glycol and/or dimethyl isosorbide.
  • Most preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and/or propylene glycol.
  • additives conventionally used in liquid fill materials for soft gelatin capsules can be included in dosage forms as described herein.
  • Such additives include antioxidants, preservatives, chelating agents, complexing agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders and/or mixtures thereof.
  • the amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired for the liquid fill.
  • the liquid fill can have a weight in the range of from about 0.200 g to about 1.600 g, or from about 0.200 g to about 1.300 g, or from about 0.400 g to about 1.200 g, or from about 0.600 g to about 0.800 g, or from about 0.800 g to about 1.000, or from about 1.000 g to about 1.200 g.
  • the liquid fill has a weight of about 0.400 g, about 0.600g, about 0.800 g, about 1.000 g, or about 1.200 g-
  • the soft gelatin capsule according to embodiments herein may be made by any suitable methods known in the art.
  • the oil and surfactant of the fill material are first thoroughly mixed, followed by addition of the pharmaceutical active and/or dietary supplement to produce a mixture of the pharmaceutical active and/or dietary supplement and surfactant in the oil.
  • the mixture is then optionally milled to produce a liquid fill wherein remaining solid pharmaceutical active and/or dietary supplement is reduced to small particles evenly distributed throughout the oil.
  • the liquid fill is then optionally subjected to deaeration to remove oxygen from the liquid fill.
  • the liquid fill may then be encapsulated in a soft gelatin capsule by a rotary die process.
  • the liquid fill may be maintained at a temperature in the range of from about 20 °C to about 30 °C, or from about 22 °C to about 28 °C, or from about 24 °C to about 26 °C, or about 25 °C.
  • dosage forms as described herein comprise a fill composition containing a moisture sensitive pharmaceutical active and a carrier, wherein the fill composition is encapsulated in a shell composition can have a stability wherein the amount of moisture sensitive pharmaceutical active in the dosage form decreases by not more than about 0% to about 10%, or not more than 10 %, 9 %, 8 %, 7 %, 6 %, 5 %, 4 %, 3 %, 2 %, 1 %, 0.5 % or 0 % at 6 months when stored at 25 °C and a relative humidity of 60% as measured by the following Dissolution and Assay methods (Stability Tests):
  • This method is applicable to the dissolution of moisture sensitive pharmaceutical actives (e.g., Aspirin) in softgel capsules.
  • moisture sensitive pharmaceutical actives e.g., Aspirin
  • the dissolution of the moisture sensitive pharmaceutical active in soft capsules is performed using USP dissolution apparatus, type 2 (Paddles).
  • the amount of moisture sensitive pharmaceutical active dissolved in the dissolution samples is determined by UPLC at the wavelength of 237 nm.
  • Moisture sensitive pharmaceutical active e.g., Reference Standard
  • Salicylic acid peak (for Aspirin) may only be present in sample chromatogram
  • Moisture sensitive pharmaceutical active e.g., Aspirin
  • peak symmetry factor is within 0.8 to 2.0
  • the working sample concentration is 11 mg/100ml
  • Salicylic acid for Aspirin
  • Area x Concentration Standard mg/lOOml
  • SDF 100
  • Moisture sensitive active e.g., Aspirin
  • Moisture sensitive pharmaceutical active e.g., Aspirin
  • UV or Photo Diode Array (PDA) detector
  • Moisture sensitive pharmaceutical active Reference Standard e.g., Aspirin
  • Moisture sensitive pharmaceutical active Approximately 1.0 min (e.g., Aspirin) retention time
  • Salicylic acid for Aspirin retention time Approximately 1.3 min Weak needle wash 10% ACN
  • the % RSD of the Moisture sensitive pharmaceutical active (e.g., Aspirin) peak areas of 6 injections is not more than (NMT) 2.0%;
  • the % RSD of the Salicylic acid (for Aspirin) peak areas of the 6 injections is not more than (NMT) 10.0%;
  • the % RSD of moisture sensitive pharmaceutical active (e.g., Aspirin) and Salicylic acid peak (for Aspirin) retention times of the 6 injections is not more than (NMT) 2.0%;
  • the symmetry factor is within 0.8 to 2.0;
  • Moisture sensitive pharmaceutical active e.g., Aspirin
  • Stock Standard Prepare in duplicate
  • 6.3.1.1 Accurately weight about 50 mg of Moisture sensitive pharmaceutical active (e.g., Aspirin) reference standard into a 50 ml volumetric flask.
  • Moisture sensitive pharmaceutical active e.g., Aspirin
  • Moisture sensitive pharmaceutical active e.g., Aspirin
  • Aspirin o/ow/w
  • Moisture sensitive pharmaceutical active e.g., Aspirin
  • Mg/Capsule Moisture sensitive pharmaceutical active
  • Moisture sensitive pharmaceutical active e.g., Aspirin
  • Content Uniformity mg/Capsule
  • Moisture sensitive pharmaceutical active e.g., Aspirin
  • Standard Peak Area x Sample Cone mg/100 ml
  • Moisture sensitive pharm. active e.g., Aspirin
  • Standard Peak Area x Sample Cone mg/100 ml
  • dosage forms as described herein comprising a fill composition containing aspirin (e.g., about 50 mg to about 150 mg, or about 100 mg) as the moisture sensitive pharmaceutical active and simethicone (e.g., about 100 mg to about 200 mg) as the carrier, wherein the fill composition is encapsulated in a shell composition comprising gelatin, titanium dioxide, propylene glycol, colloidal anhydrous silica, glycerol and purified water can have a stability wherein the amount of aspirin in the dosage form decreases by not more than about 0% to about 10%, or by not more than 10 %, 9 %, 8 %, 7 %, 6 %, 5 %, 4 %, 3 %, 2 %,
  • Also disclosed herein are methods of preparing a dosage form wherein the methods include preparing a fill composition by combining a moisture sensitive pharmaceutical active, for example, at least one of a salicylic acid or a proton pump inhibitor, with a carrier, salts thereof, esters thereof, solvates thereof and/or combinations thereof; and enclosing the fill composition within a shell composition.
  • the combining includes mixing the moisture sensitive pharmaceutical active with the carrier.
  • the mixing can be accomplished by at least one of an impeller, a pump and/or a static mixer.
  • the mixing is by an impeller at a speed of about 10 rpm to about 100 rpm.
  • the combining can be by a batch or continuous method.
  • the combining is in a tank, optionally, the material in the tank is under a nitrogen blanket or is contacted with nitrogen bubbles. In embodiments, the combining can occur for about 2 hours to about 24 hours. The combining can be performed at room temperature or at a temperature of about 20 °C to about 45 °C. In embodiments, the method can further include deaerating the fill composition before enclosing the fill composition in the shell composition.
  • the enclosing can include encapsulating the fill composition within the shell composition.
  • the enclosing can be by an encapsulation apparatus.
  • known methods typically use gel systems containing, primarily, gelatin as the structuring matrix, polyols such as glycerin to provide a plasticizer function, and water as the solvent.
  • a traditional technology for manufacturing soft gelatin capsules is a rotary die process for producing soft gelatin capsules in a continuous manufacturing process.
  • An example of a rotary die manufacturing process of soft capsules is disclosed in detail in Ebert, W. R.,“Soft elastic gelatin capsules: a unique dosage form”, Pharmaceutical Tech., October 1977; Stanley, J. P.,“Soft Gelatin Capsules”, in The Theory and Practice of Industrial Pharmacy (Lachman, Lieberman and Kanig, Editors), 3rd Edition, published by Lea & Febiger, U.S. Pat.
  • the fill matrix is prepared by adding simethicone at a viscosity of about 570 cps and a drug (e.g., acetylsalicylic acid powder) to a vessel.
  • a drug e.g., acetylsalicylic acid powder
  • the mixture is stirred to form a uniform dispersion.
  • the mixture can be deaerated under vacuum.
  • the soft capsule shells can be prepared from a gel mass, which is formed by adding glycerol, purified water and gelatin into a vessel.
  • the resulting glycerol-gelatin mixture is heated and mixed under vacuum. Once mixed, the vacuum is released and the resulting gel mass is discharged into a holding vessel of a softgel encapsulation apparatus.
  • a coloring agent can be added to the gel mass and mixed while in the holding vessel.
  • the gel mass is used by an encapsulation apparatus to encapsulate the fill matrix and form softgel capsules.
  • the softgel capsules are dried for a period of time following encapsulation and then are bulk packaged and subsequently unit packaged.
  • dosage forms as described herein can be used in a method of treating pain, comprising: administering to a patient in need thereof a dosage form as described herein, for example, containing a pain medication such as aspirin.
  • dosage forms as described herein can also be used in a method of reducing fever, comprising: administering to a patient in need thereof a dosage form as described herein containing, for example, a fever reducer medication (e.g., aspirin).
  • Dosage forms as described herein can also be used in a method of reducing and/or preventing blood clots, comprising: administering to a patient in need thereof a dosage form as described herein containing, for example, a pharmaceutical active for reducing blood clots (e.g., aspirin).
  • Dosage forms as described herein can also be used in a method of treating arthritis, comprising: administering to a patient in need thereof a dosage form as described herein containing a pain medication (e.g., aspirin).
  • Dosage forms as described herein can also be used in a method of treating at least one of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, symptomatic endoscopy negative reflux disease, laryngopharyngeal reflux causing laryngitis, chronic cough, Barrett’s esophagus, eosinophilic esophagitis, stress gastritis, ulcers and/or gastrinomas, comprising: administering to a patient in need thereof a dosage form as described herein containing a pharmaceutical active suitable for treating any of these conditions (e.g., aspirin, a proton pump inhibitor and/or a calcium channel blocker).
  • a pharmaceutical active suitable for treating any of these conditions e.g., aspirin, a proton pump inhibitor and/or a calcium channel blocker.
  • Dosage forms as described herein can also be used in a method of reducing stomach acid production, comprising: administering to a patient in need thereof a dosage form as described herein containing a pharmaceutical active for reducing stomach acid production (e.g., a proton pump inhibitor).
  • Dosage forms as described herein can also be used in a method of treating at least one of heart disease, hypertension, high blood pressure, coronary artery disease, coronary spasm, angina, abnormal heart rhythm, hypertrophic cardiomyopathy, diastolic heart failure and/or Raynaud’s syndrome, comprising: administering to a patient in need thereof a dosage form as described herein containing a pharmaceutical active for treating these conditions (e.g., a calcium channel blocker).
  • a pharmaceutical active for treating these conditions e.g., a calcium channel blocker
  • Softgel dosage forms each containing an aspirin fill matrix were prepared.
  • the compositions of the aspirin fill matrix and the soft capsule shell are set forth in Table 1.
  • Aspirin in powder form was dissolved in the simethicone in a vessel. The solution was stirred for about 10 minutes and subsequently deaerated under vacuum.
  • a gel mass for the soft capsule shell was prepared by adding the glycerol, purified and gelatin into a vessel. The mixture was placed under vacuum. After releasing the vacuum, the gel mass was discharged into a holding vessel. Shell colors were added and mixed until fully dispersed.
  • the aspirin fill matrix was encapsulated in soft capsule shells using a typical encapsulation device.
  • the resulting aspirin softgel dosage forms were subsequently dried, bulk packaged and unit packaged.
  • the stability of the aspirin softgel capsules was evaluated over a period of twelve (12) months.
  • the dissolution and assay methods disclosed above were followed.
  • dissolution of the Aspirin in soft capsules was performed using USP dissolution apparatus, type 2 (Paddles).
  • the amount of Aspirin dissolved in the dissolution samples was determined by UPLC at the wavelength of 237 nm.
  • a dissolution medium i.e., a pepsin solution
  • Tween 85 20 g was mixed with 20 g of Triton X-100 in a 1-1 container over a hot water bath.
  • the pepsin solution was dissolved in the hot solution and diluted to volume.
  • the mixture was sonicated to de-gas before use.
  • the de-gassed solution in an amount of 100 ml was mixed with 28.8 g of Pepsin to form a pepsin solution.
  • An amount of 890 mL of the de-gassed solution was placed in six (6) dissolution vessels of a USP Type 2 (Paddles) apparatus and equilibrated to at a temperature of 37°C ⁇ 0.5°C.
  • Pepsin solution in an amount of 10 mL was added to each of the six (6) dissolution vessels and the apparatus was operated at a speed of 125 rotations per minute. About 10 mL of the samples was collected and filtered through a 0.2 pm RC syringe filter. The final working sample concentration is 11 mg/100 mL.
  • Table 2 provides the stability data for the softgel dosage forms. As shown in Table 2, the softgel dosage forms remained stable without measurable degradation when stored at 25 °C and 60 % RH for 6 months.
  • the resulting softgel dosage form provided a robust, stable aspirin dosage form. Without being bound by any particular theory, it is believed that the aspirin in the aspirin fill matrix is protected from moisture migration from or through the soft capsule shell after it has been blended uniformly with the simethicone at a desired viscosity. The viscosity of the final aspirin fill matrix ensures that there is no issue with dissolution during shelf life.
  • Example 1 The stability results of the aspirin softgel dosage forms from Example 1 can be compared with other softgel aspirin formulations having different carriers.
  • the stability results for the other formulations are presented in Tables 3-6. As shown, the dosage forms of Example 1 provide unexpectedly superior stability results.

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Abstract

L'invention concerne des formes galéniques stables, par exemple, des formulations de capsules stables constituées d'au moins un agent pharmaceutique actif sensible à l'humidité (par exemple, un acide salicylique, un inhibiteur de la pompe à protons, un inhibiteur des canaux calciques, des sels de ceux-ci, des esters de ceux-ci, des solvates de ceux-ci et/ou des associations de ceux-ci) qui empêchent la migration du produit pharmaceutique sensible à l'humidité dans l'enveloppe et/ou la migration de l'humidité dans la composition de charge. L'invention concerne également des procédés de préparation de telles formes galéniques et leurs procédés d'utilisation.
PCT/US2020/041930 2019-07-15 2020-07-14 Formes galéniques capsules, leurs procédés de préparation et leurs procédés d'utilisation WO2021011538A1 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
CN115166102A (zh) * 2022-08-11 2022-10-11 中国医学科学院药用植物研究所海南分所 硫酸软骨素和氨基葡萄糖及其衍生物的uplc-pda测定方法
WO2023244533A1 (fr) * 2022-06-13 2023-12-21 R.P. Scherer Technologies, Llc Capsule molle de bisacodyl entérique
WO2024035911A1 (fr) * 2022-08-12 2024-02-15 R.P. Scherer Technologies, Llc Capsules à enveloppe molle à dissolution rapide

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