WO2013155430A1 - Soft elastic capsules containing tablets and liquid or semisolid fills and methods for their manufacture - Google Patents
Soft elastic capsules containing tablets and liquid or semisolid fills and methods for their manufacture Download PDFInfo
- Publication number
- WO2013155430A1 WO2013155430A1 PCT/US2013/036396 US2013036396W WO2013155430A1 WO 2013155430 A1 WO2013155430 A1 WO 2013155430A1 US 2013036396 W US2013036396 W US 2013036396W WO 2013155430 A1 WO2013155430 A1 WO 2013155430A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- capsule
- soft elastic
- active ingredient
- film
- elastic capsule
- Prior art date
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- 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
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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Definitions
- Combination therapies are employed in treating many types of diseases.
- the dosage forms of two or more of the prescribed or desired active agents are incompatible with each other. Due to this limitation, the active agents are required to be administered separately, which can lead to poor compliance with treatment regimens due to the number of pills and liquids that must be consumed.
- the soft elastic capsule can be an acid resistant, capsule shell that defines an encapsulated space having a predetermined volume, a liquid or semisolid fill comprising a first active ingredient located within the encapsulated space, and a first compressed tablet.
- the first compressed tablet is located within the encapsulated space, can be unanchored to the capsule shell, and can be surrounded by the fill.
- the tablet is substantially insoluble in the fill.
- the first compressed tablet can have a minimal dimension of 2 mm (e.g., a minimal dimension of 5 mm). In some embodiments, the first compressed tablet has a maximum dimension of 16 mm.
- the volume of the tablet can optionally be at least 25% smaller than the volume of the encapsulated space.
- the volume ratio of the first compressed tablet to the liquid or semisolid fill can be from 1 :0.25 to 1 : 100.
- the fill is liquid.
- the capsule shell has only one compartment.
- the first active ingredient and/or the second active ingredient is a pharmaceutical, a nutraceutical, a vitamin, a mineral, or a diagnostic agent.
- the first active ingredient can be a pharmaceutically active ingredient dissolved in a
- the pharmaceutically acceptable oil-based liquid vehicle and the second active ingredient can be a pharmaceutically active ingredient.
- the first active ingredient is different from the second active ingredient.
- the first active ingredient is a polyunsaturated fatty acid (e.g., an omega-3 fatty acid) and the second active ingredient is acetylsalicylic acid, a statin (e.g., atorvastatin), clopidogrel, phytosterol, coenzyme Q10, resveratrol, bexarotene, or a combination of bexarotene and a statin.
- the first active ingredient is diphenhydramine and the second active ingredient is loratadine.
- the first active ingredient is simethicone and the second active ingredient is loperamide.
- the first active ingredient is an anti- allergy agent (e.g., cetirizine, loratadine, fexofenadine, diphenhydramine, levocetirizine, and desloratadine) and the second active ingredient is pseudoephedrine.
- the first active ingredient is a serotonin 5-HT1 A partial agonist or a selective serotonin re-uptake inhibitor and the second active ingredient is buproprion.
- the first active ingredient is metformin and the second active ingredient is miglitol or pioglitazone.
- the first active ingredient is lubiprostone and the second active ingredient is an opioid (e.g., oxycodone, hydrocodone, or morphine).
- the capsule shell can be formed of a film-forming natural polymer.
- the film-forming natural polymer can include gelatin.
- the film-forming natural polymer can include carrageenan and/or starch.
- the film-forming natural polymer can be from about 20% to about 50% by weight of the capsule shell.
- the capsule shell includes an enteric coating layer.
- the capsule shell can further be formed of a gastric resistant natural polymer, which can optionally include pectin and/or alginate.
- the concentration of the gastric resistant natural polymer can be from about 2% to about 10% by weight of the capsule shell.
- the capsule shell can be further formed of a gelling agent.
- the gelling agent can include, for example, a divalent cation salt (e.g., calcium salts and/or magnesium salts). In some examples, the concentration of the gelling agent is less than about 2% by weight of the capsule shell.
- the capsule shell can be formed of a film-forming synthetic polymer. In some examples, the film-forming synthetic polymer can be selected from the group consisting of methacrylate, ethyl acrylate, cellulose acetate phthalate, polyvinyl acetate phthalate, or a combination of these.
- the capsule shell can further include one or more plasticizers selected from the group consisting of glycerin, sorbitol, sorbitan, maltitol, glycerol, polyethylene glycol, polyalcohols with 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate, and combinations thereof.
- the concentration of the one or more plasticizers is from about 8% to about 40% by weight of the capsule shell.
- the soft elastic capsule can further comprise a second compressed tablet, which can optionally comprise a third active ingredient.
- the second active ingredient is incompatible with the first active ingredient.
- the capsule shell can be transparent or translucent.
- the compressed tablet is coated with a delayed-release coating or a sustained-release coating.
- the soft elastic capsule comprises one or more pharmaceutically acceptable excipients.
- Also described herein is a method of manufacturing a soft elastic capsule.
- the method comprises (a) forming a continuous first film comprising a film-forming polymer on a first rotating encapsulation die, (b) forming a continuous second film comprising a film-forming polymer on a second rotating encapsulation die, (c) rotating the first rotating encapsulation die and the second rotating encapsulation die in counter directions to contact the first film and second film and form a partially closed capsule, (d) providing a first compressed tablet in the partially closed capsule, (e) injecting a liquid or semisolid fill into the partially closed capsule, (f) sealing the partially closed capsule to form a soft capsule, and (g) drying and finishing the soft capsule.
- the providing step (d) comprises (dl) positioning a first compressed tablet onto the first film on the first encapsulation die, and (d2) optionally positioning a second compressed tablet onto the second film on the second encapsulation die.
- said step (c) of rotating the first rotating encapsulation die and the second rotating encapsulation die in counter directions to contact the first film and second film and form a partially closed capsule provides the first compressed tablet and the optional second compressed tablet in the partially closed capsule.
- Step (dl) can comprise positioning a first compressed tablet onto the first film and into a die cavity on the first encapsulation die and step (d2) can comprise optionally positioning a second compressed tablet onto the second film and into a die cavity on the second encapsulation die.
- the providing step (d) can comprise feeding the first compressed tablet and optionally a second compressed tablet into the partially closed capsule after said rotating step (c).
- the method can further comprise providing an encapsulation wedge adjacent the location where the first film and second film are contacted.
- the first compressed tablet is fed through the encapsulation wedge.
- the liquid or semisolid fill is injected through the encapsulation wedge.
- the encapsulation wedge is heated.
- the first compressed tablet and the optional second compressed tablet are pre-manufactured.
- the film- forming polymer in the first film and the second film is a natural film-forming polymer.
- the natural film-forming polymer in the first film and the second film comprises gelatin.
- the steps of forming the first film and forming the second film comprise preparing a solution comprising gelatin, a gastric-resistant natural polymer, and optionally one or more plasticizers to form a gel mass; and forming the gel mass into the first film and the second film.
- the gastric-resistant natural polymer includes pectin and/or alginate.
- the liquid or semisolid fill comprises a first active ingredient
- the first compressed tablet comprises a second active ingredient
- the second compressed tablet comprises a third active ingredient. The first active ingredient, the second active ingredient, and the third active ingredient can be different from each other.
- Figure 1 A is a schematic depicting a soft elastic capsule containing a liquid or semisolid fill and a single tablet.
- Figure IB is a schematic depicting a soft elastic capsule containing a liquid or semisolid fill and multiple tablets.
- Figure 2 is a schematic of a rotary die process for manufacturing soft elastic capsules containing a liquid or semisolid fill and one tablet. An enlarged tablet is depicted in the bottom right corner.
- Figure 3 is a schematic of a rotary die process for manufacturing soft elastic capsules containing a liquid or semisolid fill and two tablets. An enlarged tablet is depicted in the bottom right corner.
- Figure 4 is a schematic of an alternative rotary die process for manufacturing soft elastic capsules containing a liquid or semisolid fill and one tablet provided from a hopper located distal to the liquid or semisolid fill injector. An enlarged tablet is depicted in the bottom right corner.
- Figure 5 is a schematic of an alternative rotary die process for manufacturing soft elastic capsules containing a liquid or semisolid fill and two tablets provided from hoppers located distal to the liquid or semisolid fill injector. An enlarged tablet is depicted in the bottom right corner.
- Figure 6 is a schematic of an alternative rotary die process for manufacturing soft elastic capsules containing a liquid or semisolid fill and one tablet provided from a hopper adjacent the encapsulation wedge.
- the soft elastic capsules can include an acid resistant capsule shell that defines an encapsulated space having a predetermined volume, a liquid or semisolid fill comprising a first active ingredient located within the encapsulated space, and a first compressed tablet having a minimal dimension of 2 mm, being located within the encapsulated space, unanchored to the capsule shell, and surrounded by the fill.
- the tablet is substantially insoluble in the fill.
- the soft elastic capsules disclosed herein include dosage forms of active ingredients and excipients encapsulated by a film- forming composition (i.e., a capsule shell). As described above, the capsule shell defines an encapsulated space having a predetermined volume.
- the capsule shell of the soft elastic capsule disclosed herein can be acid resistant. As used herein, “acid resistant” refers to the enteric property of the capsule. Specifically, the capsule is resistant to dissolution in stomach acid for a period of time and can therefore pass through the stomach without substantial release of the active ingredients inside the capsule. As used herein,
- substantially release refers to a release of greater than 1% of the active ingredient (e.g., 1% to 100%, 5% to 95%, 10% to 90%, 20% to 80%, 30% to 70%, or 40% to 60% of the active ingredient).
- the capsule is resistant to dissolution in stomach acid for at least 30 minutes.
- the capsule can be resistant to dissolution in stomach acid for at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 55 minutes, at least 1 hour, or at least 2 hours.
- the capsule shell can include one or more layers and can be formed from one or more components, including film-forming polymers, gastric resistant polymers, gelling agents, and plasticizers.
- the film-forming polymers can be film-forming natural polymers, film-forming synthetic polymers, film-forming semi-synthetic polymers, or mixtures thereof.
- the capsule shell described herein includes at least one film-forming natural polymer, such as gelatin, carrageenans (e.g., kappa carrageenan, iota carrageenan, and blends of these), glucomannans, starches (e.g., unmodified starch and modified pregelatinized starch), other hydrocolloids, and mixtures of these.
- the capsule shell described herein includes at least one film-forming synthetic polymer such as polyvinyl alcohol, a methacrylate polymer, an ethyl acrylate polymer, an acrylic polymer (e.g., EUDRAGIT® acrylic polymer provided by Evonik Industries; Parsippany, New Jersey), cellulose acetate phthalate, or polyvinyl acetate phthalate.
- the film-forming polymer can be from about 20% to about 50% by weight of the capsule shell.
- the film-forming polymer can be from about 25% to about 40% by weight of the capsule shell.
- the film-forming polymer is about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, or about 49% by weight of the capsule shell.
- the capsule shell can include gelatin.
- the gelatin suitable for use herein can be derived from pork skins, pork and cattle bones, or split cattle hides.
- Gelatin is a mixture of peptides and proteins produced by partial hydrolysis of collagen extracted from the skin, boiled crushed bones, connective tissues, organs, and some intestines of animals, including, for example, domesticated cattle, chicken, and pigs.
- the chemical composition of gelatin is similar to that of collagen.
- the natural molecular bonds between individual partially hydrolyzed collagen strands in gelatin are broken down into a form that can rearrange.
- Gelatin can melt to a liquid when heated and can re-solidify upon cooling.
- Gelatin forms a high viscosity solution in hot water, which sets upon cooling to form a semi-solid colloid gel.
- Gelatin solutions show viscoelastic flow and streaming birefringence. As described above, gelatin can swell and form a semi-solid material in the presence of cold water. However, gelatin is readily soluble in hot water. The solubility of the gelatin is determined by the method of manufacture. Gelatin can be dispersed in a relatively concentrated acid. Such dispersions can be stable for several days (e.g., up to 15 days) with little or no chemical changes and are suitable for coating purposes or for extrusion into a precipitating bath.
- the capsule shell can further include one or more gastric resistant polymers such as gastric resistant natural polymers, gastric resistant synthetic polymers, or mixtures thereof, to provide enteric properties to the capsule shell.
- the soft elastic capsules when ingested, will pass through the stomach without dissolving.
- the film-forming polymer can include gastric resistant properties.
- the capsule shell can include a single layer formed from a composition that includes the gastric resistant polymer or can include multiple layers including at least an outside coating layer that includes the gastric resistant polymer.
- the capsule shell can further be formed of a gastric resistant natural polymer, including a polysaccharide such as pectin and/or alginates.
- the gastric resistant polymer can be included in the capsule shell in an amount of from about 2% to about 10% by weight of the capsule shell.
- the capsule shell of the soft elastic capsule can further be formed of one or more gelling agents.
- the gelling agent can include, for example, one or more divalent cations.
- the divalent cations can be provided as divalent cation salts (e.g., calcium salts and magnesium salts).
- the concentration of the gelling agent can be greater than 0% by weight and less than about 2% by weight of the capsule shell (e.g., less than about 1.5%, less than about 1.0%, or less than about 0.5% by weight of the capsule shell).
- the capsule shell can include one or more plasticizers.
- the plasticizer can be, for example, glycerol.
- Glycerol i.e., glycerine or glycerin
- Glycerol is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations.
- Glycerol is a polyol containing three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. Glycerol is sweet-tasting and has low toxicity. For human consumption, glycerol is classified by the U.S. FDA among the sugar alcohols as a caloric macronutrient.
- the plasticizer is sorbitol.
- Sorbitol is a sugar alcohol that the human body metabolizes slowly. It can be obtained by reducing the aldehyde group of glucose to a hydroxyl group. Sorbitol is naturally found in apples, pears, peaches, and prunes.
- a special grade of aqueous sorbitol solution is used in softgel capsules as a plasticizer to prevent capsules from becoming brittle.
- sorbitol is included in capsule shells that will contain polyethylene glycol as a solvent.
- suitable plasticizers include sorbitan, maltitol, polyethylene glycol, polyalcohols with 3 to 6 carbon atoms, citric acid, citric acid esters, triethyl citrate, and combinations of these.
- the concentration of the one or more plasticizers can be from about 8% by weight to about 40% by weight of the capsule shell. In some examples, the concentration of the plasticizers is from about 10% by weight to about 30% by weight or from about 15% by weight to about 25% by weight of the capsule shell.
- the capsule shells can include one or more viscosity modifiers.
- suitable viscosity modifiers include guar gum, locust bean gum, xanthan gum, agar, and gellan gum.
- the viscosity modifier can be included in the capsule shell in an amount of greater than 0%) by weight and less than 10% by weight of the composition (e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5% by weight of the composition).
- the capsule shell can be prepared as a transparent or translucent capsule shell.
- the capsule shell can be semi-transparent, semi-opaque, or opaque.
- the opaque capsule shells are prepared using titanium dioxide, which can protect light sensitive active ingredients from degradation.
- the capsule shells can further include a colorant to color the capsules. Examples of suitable colorants include FD&C and D&C dyes, iron oxides, and natural colorants.
- the capsule can be imprinted or have a decorative coating.
- the capsule shell can be prepared to have only one compartment (i.e., the capsule shell does not contain multiple compartments).
- the capsules are multi-phasic in that the capsules contain two or more phases of matter.
- the capsules can include active ingredients in a solid phase, a semisolid phase, and/or a liquid phase.
- the soft elastic capsules disclosed herein include a liquid or semisolid fill located within the encapsulated space.
- the liquid or semisolid fill includes a first active ingredient.
- the first active ingredient can include, for example, a pharmaceutical, a nutraceutical, a vitamin, a mineral, or a diagnostic agent.
- antiperistaltic antipneumocystic, antiproliferative, antiprostatic hypertrophy, antiprotozoal, antipruritic, antipsoriatic, antirheumatic, antischistosomal, antiseborrheic, antisecretory, antispasmodic, antithrombotic, antitussive, anti-ulcerative, anti-urolithic, antiviral, appetite suppressant, benign prostatic hyperplasia therapy agent, bone resorption inhibitor,
- bronchodilator carbonic anhydrase inhibitor, cardiac depressant, cardioprotectant, cardiotonic, cardiovascular agent, choleretic, cholinergic, cholinergic agonist, cholinesterase deactivator, coccidiostat, diagnostic aid, diuretic, ectoparasiticide, enzyme inhibitor, estrogen, fibrinolytic, free oxygen radical scavenger, glucocorticoid, gonad-stimulating principle, hair growth stimulant, hemostatic, hormone, hypocholesterolemic, hypoglycemic, hypolipidemic, hypotensive, immunizing agent, immunomodulator, immunoregulator, immunostimulant, immunosuppressant, impotence therapy adjunct, inhibitor, keratolytic, LHRH agonist, liver disorder treatment, luteolysin, mucolytic, mydriatic, nasal decongestant, neuromuscular blocking agent, non-hormonal sterol derivative, oxytocic, plasminogen activator, platelet activating factor
- suitable pharmaceutical agents include those as listed in the Merck Index (13 th Edition, Wiley, 2001), The United States Pharmacopeia-National Formulary (USP-NF), and the FDA's Orange book, which are each incorporated by reference herein at least for their teachings of pharmaceutically active agents.
- nutraceuticals include, but are not limited to, amino acids, terpenoids (e.g., carotenoid terpenoids and non-carotenoid terpenoids), herbal supplements, homeopathic supplements, glandular supplements, polyphenolics, flavonoid polyphenolics, phenolic acids, curcumin, resveratrol, lignans, glucosinolates, isothiocyanates, indoles, thiosulfonates, phytosterols, anthraquinones, capsaicin, piperine, chlorophyll, betaine, oxalic acid, acetyl-L- carnitine, allantoin, androsterondiol, androsterondione, betaine (trimethylglycine), caffeine, calcium pyvurate (pyruvic acid), carnitine, carnosine, carotene, carotenoid, choline, chlorogenic acid, cholic acid, chondroitin s
- the first active ingredient can include one or more vitamins.
- vitamin refers to any organic substance which is typically essential for the normal growth and activity of humans.
- suitable vitamins include, but are not limited to, vitamin A (retinol), Bl (thiamine), B2 (riboflavin), B complex, B6 (pyridoxine), B12
- the mineral for use in the first active ingredient can be any mineral.
- Examples of minerals include, but are not limited to, boron, calcium, chromium, copper, iron, magnesium, manganese, molybdenum, nickel, phosphorus, selenium, silicon, tin, vanadium, and zinc.
- the first active ingredient can optionally include a diagnostic agent.
- Diagnostic agents include, for example, imaging agents, contrasting agents, enzymes, and fluorescent substances.
- the first active ingredient is innately a liquid or semisolid.
- the first active ingredient can be prepared as a liquid.
- Liquid active ingredients can, for example, be prepared by dissolving or otherwise mixing an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols (e.g., propylene glycol or polyethylene glycol), ethanol, fatty acids, glycerides, oils, sterols, phospholipids, and the like, to thereby form a solution.
- the active ingredient can be dispersed or suspended in the liquid carrier.
- the first active ingrediens can be prepared in a self- emulsifying/microemulsifying drug delivery system (SEDDS) system.
- SEDDS self- emulsifying/microemulsifying drug delivery system
- the SEDDS system can include an oil, a surfactant, a cosurfactant or solubilizer, and the first active ingredient.
- the liquid active ingredients can be prepared to contain the active ingredient in the range of 0.005% to 100%, with the balance made up from non-toxic carrier. Methods for preparation of these compositions are known to those skilled in the art.
- the liquid fill can contain 0.001% to 100%, 0.1% to 95%, 1% to 90%, 5% to 70%, or 10%) to 50%) by weight active ingredient.
- One or more compressed tablets are also located within the encapsulated space formed by the capsule shell.
- the one or more compressed tablets are substantially insoluble in the fill.
- “Substantially insoluble” tablets include tablets having very low chemical solubility in the fill (e.g, less than 10 g of the tablet can dissolve in 100 ml of the fill). Therefore, the tablets can retain the compressed tablet form after a period of time. For example, a substantially insoluble tablet can retain at least 90%, at least 95% or at least 99% of its form in the fill after a period of one year.
- the compressed tablets present within the encapsulated space can be unanchored to the capsule shell.
- unanchored refers to the compressed tablets being unattached to the capsule shell and thus capable of free movement throughout the encapsulated space.
- the volume of the tablet is smaller than the volume of the encapsulated space.
- the compressed tablets can be surrounded by the fill (i.e., the fill can be present on all sides of compressed tablets and in contact with the outer surface of the compressed tablet).
- the volume of the tablet is at least 25% smaller than the volume of the
- the volume of the tablet can be at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% smaller than the volume of the encapsulated space.
- the volume ratio of the compressed tablet to the liquid or semisolid fill is from 1 :0.25 to 1 : 100 (e.g., from 1 : 1 to 1 :75 or from 1 :5 to 1 :50).
- the weight ratio of the compressed tablet to the liquid or semisolid fill is from 1 :5 to 1 : 100 (e.g., from 1 : 10 to 1 :75 or from 1 :25 to 1 :50).
- the outer surface of the compressed tablet can optionally be coated with a delayed-release coating or a sustained-release coating.
- the compressed tablet is a membrane-controlled release tablet such as an
- the compressed tablet is a matrix-type controlled release tablet.
- the compressed tablet can include release rate controlling excipients within the tablet matrix.
- release rate controlling excipient includes any substance capable of slowing the release rate of the active ingredient from the compressed tablet dosage form.
- the release rate controlling excipient can be, for example, a polymer, a fatty compound, or a mixture of these.
- Suitable polymeric release rate controlling excipients include, for example, cellulose ethers (e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, carboxymethyl cellulose, crosslinked carboxymethyl cellulose and its alkali salts, ethylhydroxyethylcellulose, hydroxyethyl methylcellulose, hydrophobically modified hydroxyethyl cellulose, hydrophobically modified ethylhydroxyethylcellulose, carboxymethyl hydroxyethylcellulose, and carboxymethyl hydrophobically modified hydroxyethyl cellulose); vinyl pyrrolidone polymers (e.g., crosslinked polyvinylpyrrolidone or copolymers of vinyl pyrrolidone and vinyl acetate); alkylene oxide homopolymers (e.g., polypropylene oxide); superdisintegrant polymers (e.g
- micro crystalline cellulose and cellulose derivatives alpha-, beta-and gamma-cyclodextrin and dextrin derivatives such as cross-linked carboxymethylcellulose
- gums of plant, animal, mineral or synthetic origin e.g., agar, alginates, carrageenan, furcellaran derived from marine plants, guar gum, gum arabic, gum tragacanth, karaya gum, locust bean gum, pectin derived from terrestrial plants
- microbial polysaccharides e.g., dextran, gellan gum, rhamsan gum, welan gum, xanthan gum
- synthetic or semi-synthetic gums e.g., propylene glycol alginate, hydroxypropyl guar and modified starches such as sodium starch glycolate
- acrylic acid polymers such as cross-linked polymers or homopolymers and co-polymers of acrylate or methacrylate monomers.
- Suitable fatty compounds for use as the release rate controlling excipients include waxes (e.g., digestible, long chain (C8-C50, especially C12-C40)), substituted or unsubstituted hydrocarbons (e.g., fatty acids, fatty alcohols, glyceryl esters of fatty acids), and mineral and vegetable oils.
- waxes e.g., digestible, long chain (C8-C50, especially C12-C40)
- substituted or unsubstituted hydrocarbons e.g., fatty acids, fatty alcohols, glyceryl esters of fatty acids
- mineral and vegetable oils e.g., mineral and vegetable oils.
- the tablets as described herein can be prepared using techniques and procedures known to those of skill in this art; see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition, 1999.
- the tablets can be made, for example, by direct compression, dry granulation (e.g., by slugging or roller compaction), or wet granulation.
- Direct compression involves blending the ingredients in a blender or mixer and compressing the ingredients of the tablet directly without changing the physical and chemical properties of the active ingredients.
- Dry granulation can include the steps of blending the ingredients, slugging the ingredients, dry screening, lubrication, and compression.
- the wet granulation method can include mixing the ingredients in a suitable blender, followed by adding a granulating solution under shear (e.g., low shear or high shear) to obtain a granulation.
- the damp mass can then be screened through a suitable screen and dried by tray drying or fluidized bed drying.
- the wet mass can be dried and passed through a mill.
- tablets can have a variety of shapes.
- the tablets can be round, ovoid, polygonal, or polyhedral (e.g., triangular or
- dimension refers to the distance between two antipodal points of the tablet.
- dimension can refer to diameter in a round tablet.
- the compressed tablets have a minimal (i.e., minimum) dimension of 2 mm or greater.
- the compressed tablets can have a minimal dimension of 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, or 10 mm.
- the compressed tablets can have a maximum dimension of 16 mm or less.
- the compressed tablets can have a maximum dimension of 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, or 10 mm.
- the tablets can have convex or concave surfaces.
- the tablets can contain one or more cavities (e.g., a recess or a hole).
- the encapsulated space includes at least one compressed tablet.
- a first compressed tablet is located within the encapsulated space that includes a second active ingredient.
- the second active ingredient is a pharmaceutical, a nutraceutical, a vitamin, a mineral, or a diagnostic agent. Suitable pharmaceutical agents, nutraceuticals, vitamins, minerals, and diagnostic agents include those as described herein.
- the first active ingredient and the second active ingredient are the same to provide different release profiles.
- the first active ingredient is different from the second active ingredient.
- the second active ingredient is incompatible with the first active ingredient.
- a second compressed tablet can be located within the second compressed tablet.
- the second compressed tablet can include a third active ingredient such as a pharmaceutical, a nutraceutical, a vitamin, a mineral, or a diagnostic agent as described herein.
- One or more pharmaceutically acceptable excipients can further be encapsulated within the capsule shell.
- pharmaceutically acceptable excipients include buffers, such as phosphate buffers, citrate buffer, and buffers with other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinyl pyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine;
- chelating agents such as EDTA
- sugar alcohols such as mannitol or sorbitol
- salt- forming counterions such as sodium
- nonionic surfactants such as TWEEN ® (ICI, Inc.; Bridgewater, New Jersey), polyethylene glycol (PEG), and PLURONICSTM (BASF; Florham
- Diluents commonly used in the art can also be encapsulated within the shell, including water or other solvents, solubilizing agents, and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
- solubilizing agents as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-but
- first active ingredients and second active ingredients are contemplated herein.
- the first active ingredient is a pharmaceutically active ingredient dissolved in a pharmaceutically acceptable oil-based liquid vehicle and the second active ingredient is a pharmaceutically active ingredient.
- the first and second active ingredients are combined in a manner to provide a combination therapy for treating a specific disease, illness, condition, or ailment.
- a polyunsaturated fatty acid such as an omega-3 fatty acid
- acetylsalicylic acid i.e., aspirin
- the aspirin can include an enteric coating.
- a further combination of agents suitable for treating or preventing cardiovascular conditions includes a polyunsaturated fatty acid and a statin (e.g., atorvastatin) as the first and second active ingredients, respectively.
- a combination of agents suitable for treating or preventing cardiovascular conditions includes a polyunsaturated fatty acid as the first active ingredient and clopidogrel as the second active ingredient.
- a combination of agents includes a polyunsaturated fatty acid as the first active ingredient and one or more of phytosterol, coenzyme Q10, or resveratrol as the second active ingredient.
- a combination of agents can further include a polyunsaturated fatty acid as the first active ingredient and bexarotene, a statin, or a combination of bexarotene and a statin as the second active ingredient, and can be used to treat age related dementia (e.g., Alzheimer's Disease).
- the first active ingredient is diphenhydramine and the second active ingredient is loratadine.
- the first active ingredient is simethicone and the second active ingredient is loperamide.
- the first active ingredient can be an anti-allergic (i.e., anti-allergy agent) and the second active ingredient can be pseudoephedrine.
- the pseudoephedrine can be, for example, in an immediate release form or a controlled release form.
- exemplary anti-allergy agents include cetirizine, loratadine, fexofenadine, diphenhydramine, levocetirizine, and desloratadine.
- a soft elastic capsule containing a serotonin 5-HT1 A partial agonist or a selective serotonin re-uptake inhibitor as the first active ingredient and buproprion as the second active ingredient can be used, for example, to treat depressive disorders.
- a soft elastic capsule including metformin as the first active ingredient and miglitol or pioglitazone as the second active ingredient can be used to improve glycemic control of subjects.
- the soft elastic capsule can include lubiprostone as the first active ingredient and an opioid as the second active ingredient.
- suitable opioids include, for example, oxycodone, hydrocodone, or morphine.
- Soft elastic capsules including these combinations of active ingredients can be used to treat, for example, irritable bowel syndrome and constipation.
- the opioid is oxycodone.
- Also described herein is a method of manufacturing a soft elastic capsule.
- the method includes the steps of (a) forming a continuous first film comprising a film-forming polymer on a first rotating encapsulation die; (b) forming a continuous second film comprising a film- forming polymer on a second rotating encapsulation die; (c) rotating the first rotating encapsulation die and the second rotating encapsulation die in counter directions to contact the first film and second film and form a partially closed capsule; (d) providing a first compressed tablet in the partially closed capsule; (e) injecting a liquid or semisolid fill into the partially closed capsule; (f) sealing the partially closed capsule to form a soft capsule; and (g) drying and finishing the soft capsule.
- the continuous first film and continuous second film can be prepared by combining and mixing ingredients used to form a capsule shell, as disclosed herein.
- the continuous first and second films can include film-forming polymers, gastric resistant polymers, gelling agents, and plasticizers.
- the film-forming polymer in the first film and the second film is a natural film-forming polymer as described herein.
- the first film and the second film include gelatin.
- the first film and second film are formed by preparing a solution comprising gelatin, a gastric-resistant natural polymer, and optionally one or more plasticizers to form a gel mass, and forming the gel mass into the first film and the second film.
- the gastric-resistant natural polymer can include, for example, pectin or alginate.
- the first film and second film can be cast individually on separate rotating casting drums in a continuous manner by introducing the gel mass to an outer casting surface of each drum.
- the cooling drums can be cooled to a temperature lower than the gel mass, which can cause the gel mass to solidify on the drum casting surface to form the films.
- the gel mass can be dispensed in a layer in an amount sufficient to provide the desired thickness of the film.
- the thickness of the film can range, for example, from 0.005 inches to 0.045 inches.
- the first and second films can then be fed from the casting drums to the first and second rotating
- Figures 1A and IB illustrate soft elastic capsules as described herein.
- Figure 1A illustrates an embodiment where the soft elastic capsule 10 includes a capsule shell 12, such as an acid resistant capsule shell, and a liquid or semi-solid fill 14 that surrounds a tablet 16.
- a capsule shell 12 such as an acid resistant capsule shell
- a liquid or semi-solid fill 14 that surrounds a tablet 16.
- Figure IB illustrates another embodiment where the soft elastic capsule 20 includes a capsule shell 22, such as an acid resistant capsule shell, and a liquid or semisolid fill 24 that surrounds multiple tablets 26, 28, 30, and 32.
- a capsule shell 22 such as an acid resistant capsule shell
- a liquid or semisolid fill 24 that surrounds multiple tablets 26, 28, 30, and 32.
- Figure 2 illustrates an embodiment for making the soft elastic capsules described herein.
- a continuous film 40 and a continuous film 42 can be fed over tractor rolls 44 and 46, respectively.
- the tractor rolls 44 and 46 optionally can be coated with a lubricant.
- the continuous film 40 advances from the tractor roll 44 to a rotating encapsulation die 48.
- the continuous film 42 advances from the tractor roll 46 to a rotating encapsulation die 50.
- the encapsulation dies 48 and 50 rotate in opposite directions. For example, as shown in Figure 2, the encapsulation die 48 can rotate counterclockwise while the encapsulation die 50 can rotate clockwise.
- a layer of lubricant from the tractor rolls 44 and 46 can be retained on the reverse surface of the films 40 and 42, respectively, to prevent the encapsulation dies 48 and 50 from sticking to the films 40 and 42upon contact.
- an encapsulation wedge 52 can be provided adjacent the location where the films 40 and 42 contact the encapsulation dies 48 and 50 as further described herein. In some embodiments, the encapsulation wedge 52 can be heated.
- the first and second encapsulation dies 48 and 50, together with an encapsulation wedge 52 can be symmetrically disposed relative to each other about a center plane A of the apparatus. The films 40 and 42 are advanced between the encapsulation wedge 52 and the encapsulation dies 48 and 50, respectively.
- a surface 54 of the film 40 and a surface 56 of the film 42 contact the encapsulation wedge 52 and a reverse surface 58 of the first film 40 and a reverse surface 60 of the film 42 contact the encapsulation dies 48 and 50, respectively.
- the rotating encapsulation die 48 and the rotating encapsulation die 50 rotate to advance the film 40 and the film 42 together to form a partially closed capsule 62.
- the compressed tablet 64 can be released from a tablet hopper 66 into the partially closed capsule 62.
- the compressed tablet 64 can be pre-manufactured (i.e., compressed and formed into a tablet prior to being provided in the tablet hopper 66).
- the tablet hopper 66 is provided in the encapsulation wedge 52 and the tablet 64 is released from the tablet hopper into the partially closed capsule 62.
- a liquid or semisolid fill 68 can be injected from a pump through a channel 70 into the partially closed capsule 62, for example, after the tablet 64 has been provided in the partially closed capsule.
- the channel 70 can be provided in the
- the partially closed capsule 62 can be sealed to form a soft elastic capsule 72 as described herein.
- the soft elastic capsule can then be dried and finished according to methods known in the art.
- the soft elastic capsule can include more than one tablet.
- Figure 3 is similar to Figure 2 but includes a second tablet hopper 80 for releasing a second compressed tablet 82 into a partially closed capsule 84.
- the second compressed tablet 82 can be pre- manufactured and can be released into the partially closed capsule 84 simultaneously with, before, or after the liquid or semisolid fill 68 and the compressed tablet 64.
- the partially closed capsule 84 can then be sealed as described above to form a soft capsule 86 containing multiple tablets 64 and 82.
- the process of Figure 3 provided one method of providing multiple tablets in the same soft elastic capsule, other means can also be used.
- more than one tablet can be released from the tablet hopper 66 illustrated in Figure 2 (or Figure 3).
- Figures 4 and 5 illustrate alternative embodiments of producing the soft elastic capsules described herein.
- a tablet hopper 90 feeds a compressed tablet 92 into a die cavity 94 located on encapsulation die 48.
- the tablet 92 is released from the tablet hopper 90 and positioned onto the surface 54 of the film 40.
- the tablet hopper 90 is located on an end of the encapsulation wedge 52 distal to the center plane A of the apparatus.
- the positioning of the tablet 92 forms an indentation in the film 40 into the die cavity 94.
- the tackiness of the surface 54 and the encapsulation wedge 52 keep the tablet 92 on the film 40.
- the tablet 92 is provided in the partially closed capsule 96 formed by the film 40 and the film 42.
- the liquid or semisolid fill 68 can be fed from channel 70 as described above into the partially closed capsule 96.
- the partially closed capsule 96 can then be sealed as described above to form a soft capsule 98 containing the tablets 92 and the fill 68.
- a second tablet hopper 100 can optionally be provided in the same manner as tablet hopper 90 to provide a second tablet 102.
- the second compressed tablet 102 can be situated in a die cavity 104 located on encapsulation die 50.
- the tablet 102 is released from the tablet hopper 100 and positioned onto the surface 56 of the film 42.
- the tablet hopper 100 can be located on an end of the encapsulation wedge 52 opposite the tablet hopper 90.
- the positioning of the second tablet 102 forms an indentation in the film 42 into the die cavity 104 and is then advanced to be provided in the partially closed capsule 106 formed by the film 40 and the film 42.
- the tablet 92 and the liquid or semisolid fill 68 can also be fed as described above into the partially closed capsule 106.
- the partially closed capsule 106 can then be sealed as described above to form a soft capsule 108 containing tablets 92 and 102 and the fill 68.
- the tablet 92 can be dispensed from a tablet hopper 110, located adjacent to the encapsulation wedge 52, onto the film 40 as illustrated in Figure 6.
- the tablet 92 is released from the tablet hopper 110 and positioned on the surface 54 of the film 40.
- the die 48 rotates to the position of the ejector pin 112 and the tablet 92 is positioned into the die cavity 94 located on die 48.
- the liquid or semisolid fill 68 can be fed from channel 70, through the encapsulation wedge 52, into the partially closed capsule 96 and sealed to form the soft capsule 72.
- the soft capsule 72 is released from the encapsulation dies 48 and 50 located on the encapsulation dies.
- the strength of the capsule shell can be tested using methods known to those of skill in this art.
- the strength of the gelatin used to form a soft capsule as described herein can be determined by measuring the Bloom strength.
- the Bloom strength test determines the force (e.g., in grams) needed by a probe to deflect the surface of the gel without breaking it.
- the cylindrical probe used for the test has a diameter of about 0.5 inch and the deformation of the gel tested can be about 4 mm.
- the result is expressed in Bloom (grams).
- Gels suitable for use as the capsule shell have a Bloom strength between 30 and 300 Bloom (e.g., between 100 and 200 Bloom).
- Capsule Shell Composition 1 includes pectin as a gastric resistant polymer.
- Capsule Shell Composition 2 a film-forming polymer for use as a capsule shell.
- Capsule Shell Composition 2 includes EUDRAGIT L 100, an anionic copolymer based on methacrylic acid and methyl methacrylate (Evonik Industries; Essen, Germany).
- Examples 1-4 were prepared using a rotary die process as described herein.
- the capsule shells were prepared from either Capsule Shell Composition 1 or 2, as indicated in the table above.
- Example 1 contained a fish oil fill and an enteric-coated aspirin tablet.
- Example 2 contained a fish oil fill and an atorvastatin tablet.
- Example 3 contained a diphenhydramine fill and a loratadine tablet.
- Example 4 contained simethicone as the fill and loperamide as the tablet. The amounts of each of the components are shown in the table above.
- the chemical stability of the aspirin in the fish oil fill of Example 1 under different storage conditions over time was determined and is reported in Table 1 as a percentage of the active ingredient left as compared with the label claim.
- RH refers to relative humidity. Table 4
- Examples 5-14 are prepared using a rotary die process as described herein.
- the capsule shells are prepared from either Capsule Shell Composition 1 or 2 (see Tables 1 and 2). The amounts of each of the components are shown in the table above.
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Abstract
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201380019629.4A CN104254323A (en) | 2012-04-13 | 2013-04-12 | Soft elastic capsules containing tablets and liquid or semisolid fills and methods for their manufacture |
CA2868326A CA2868326A1 (en) | 2012-04-13 | 2013-04-12 | Soft elastic capsules containing tablets and liquid or semisolid fills and methods for their manufacture |
JP2015505947A JP2015512945A (en) | 2012-04-13 | 2013-04-12 | Soft elastic capsule containing tablet and liquid or semi-solid filler, and method for producing the same |
EP13719332.2A EP2844235A1 (en) | 2012-04-13 | 2013-04-12 | Soft elastic capsules containing tablets and liquid or semisolid fills and methods for their manufacture |
MX2014011139A MX2014011139A (en) | 2012-04-13 | 2013-04-12 | Soft elastic capsules containing tablets and liquid or semisolid fills and methods for their manufacture. |
Applications Claiming Priority (2)
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US201261623737P | 2012-04-13 | 2012-04-13 | |
US61/623,737 | 2012-04-13 |
Publications (1)
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WO2013155430A1 true WO2013155430A1 (en) | 2013-10-17 |
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Family Applications (1)
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---|---|---|---|
PCT/US2013/036396 WO2013155430A1 (en) | 2012-04-13 | 2013-04-12 | Soft elastic capsules containing tablets and liquid or semisolid fills and methods for their manufacture |
Country Status (7)
Country | Link |
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US (2) | US20130280323A1 (en) |
EP (1) | EP2844235A1 (en) |
JP (1) | JP2015512945A (en) |
CN (1) | CN104254323A (en) |
CA (1) | CA2868326A1 (en) |
MX (1) | MX2014011139A (en) |
WO (1) | WO2013155430A1 (en) |
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WO2014168736A1 (en) * | 2013-03-15 | 2014-10-16 | Nutramax Laboratories, Inc. | Sulforaphane/sulforaphane precursor and phytosterol/phytostanol compositions |
WO2015066176A1 (en) | 2013-10-30 | 2015-05-07 | Banner Life Sciences, LLC | Enteric soft capsules comprising polyunsaturated fatty acids |
US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US9707184B2 (en) | 2014-07-17 | 2017-07-18 | Pharmaceutical Manufacturing Research Services, Inc. | Immediate release abuse deterrent liquid fill dosage form |
CN108434116A (en) * | 2017-02-16 | 2018-08-24 | 人福普克药业(武汉)有限公司 | Bei Saluoting soft capsules and preparation method thereof |
US10172797B2 (en) | 2013-12-17 | 2019-01-08 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US10195153B2 (en) | 2013-08-12 | 2019-02-05 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
EP3412280A4 (en) * | 2016-02-05 | 2019-08-28 | Korea United Pharm. Inc. | Oral composite formulation comprising fat-soluble drug and solid preparation coated with oil repellent base |
US10959958B2 (en) | 2014-10-20 | 2021-03-30 | Pharmaceutical Manufacturing Research Services, Inc. | Extended release abuse deterrent liquid fill dosage form |
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EP3738586A1 (en) | 2013-10-30 | 2020-11-18 | Patheon Softgels Inc. | Enteric soft capsules comprising polyunsaturated fatty acids |
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US11033505B2 (en) | 2016-02-05 | 2021-06-15 | Korea United Pharm, Inc. | Oral complex preparation comprising fat-soluble drug and solid preparation coated with oil-proof material |
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CN108434116B (en) * | 2017-02-16 | 2021-05-11 | 人福普克药业(武汉)有限公司 | Bexarotene soft capsule and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
CA2868326A1 (en) | 2013-10-17 |
EP2844235A1 (en) | 2015-03-11 |
JP2015512945A (en) | 2015-04-30 |
MX2014011139A (en) | 2015-07-17 |
US20130280323A1 (en) | 2013-10-24 |
CN104254323A (en) | 2014-12-31 |
US20150238429A1 (en) | 2015-08-27 |
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