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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
  • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
• • 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
  • A61K9/20—Pills, tablets, discs, rods
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Definitions

• This invention relates to solid, transparent or semi-transparent, pharmaceutically acceptable preparations (troches, lozenges) comprising one or more matrix-forming materials in which are entrapped small particles which contain at least one beneficial agent.
• This presentation interdicts tampering with the particles and their active agent and makes the preparations more tamper evident and tamper proof.
• Troches also known as lozenges or pastilles, are disc-shaped solids containing a medical agent in a suitably flavored base.
• the base may be a hard sugar candy, glycerinated gelatin or the combination of sugar with sufficient mucilage to provide stability to a shape or form. These products are placed in the mouth where they slowly dissolve, liberating the active ingredient.
• Troches can be prepared extemporaneously by a trained and licensed formulator.
• a classic method is to add water to a mixture of powdered drug, sugar and a gum until a pliable mass is obtained. This mass is shaped into roll and pieces are cut from this cane.
• Heat-stable compounds can be formulated into a hard candy base; such preparations are usually called lozenges.
• a sugar syrup, with or without a binder is concentrated over heat until it becomes a pliable mass at which point the active is added and the mixture is kneaded while warm to form a homogeneous mass. This warm mass is then processed through a mold to give shape to product which is cooled thus forming the hard candy. Compression-based manufacturing has been used to prepare troches containing heat-labile ingredients.
• This invention provides an advance in this art by providing a troche-like preparation as a carrier means for particulates, particularly beadlets, whereby the native condition of the beadlets can be observed through the matrix-forming material, in addition to the fact the integrity of the troche-like product can be observed at any point after manufacture or packaging.
• This invention comprises a pharmaceutically acceptable preparation comprising at least one pharmaceutically acceptable transparent or semi-transparent solid matrix-forming material in which are entrapped small particles which contain at least one beneficial agent.
• this invention relates to a process for manufacturing these products using injection molding.
• the finished product is a pharmaceutical preparation comprising some type of matrix- forming, edible material in which are entrapped small particles which comprise or contain an active agent
• the matrix-forming material is some edible material which is a solid at ambient temperature and is transparent, or semi-transparent to a degree that is no greater than what allows the user to view some or all of the entrapped particles when viewed under normal lighting conditions by the naked eye.
• Lozenge and troche preparations are illustrations of preparations within the scope of this invention. The compositional make-up of troche and lozenge preparations can be found in such texts as Remington's Pharmaceutical Sciences. 18th Ed., Mack Publishing Co., Easton, PA, USA, pp 1644-1665 (1990) and Sugar Confectionery Manufacture.
• the matrix may be formed using one compound, for example a wax or a sugar or a mixture of materials can be employed. Mixtures may comprise two or more materials from the same class of compounds, such as mixed sugars, or may be a mixture of compounds from two or more classes such as a sugar, a wax and a polyol.
• mixtures may be used in a way that causes them to retain their original identity, or they may be transformed during the manufacturing process to a second form representing a combining of subunits into a different chemical entity such as happens when polymerization or cross-linking occurs.
• Preferred matrix-forming materials are sugars and edible waxes.
• Sugars such as sucrose, dextrose, fructose, sorbitol, lycasin and other simple and complex carbohydrates which can be used to form lozenges are preferred.
• Waxes such as white wax, gelucires, carnauba wax, hydrogenated vegetable oils, Labrafils, Compritol 888 ATO, Precirol, polyethylene glycols, bees wax, paraffins, microcrystalline wax, acetylated monoglycerides, cetyl alcohol, and glyceryl monostearate.
• White wax is a particularly prefe ⁇ ed matrix- forming agent for use in this invention.
• Non-disintegrating matrices can be formed using hydrophoibic matrix- forming materials described above.
• Disintegrating matrices can be formed using a combination of hydrophilic and hydrophobic matrix forming materials; these are represented by the list of materials given above. The ratio of hydrophobic to hydrophilic materials can be adjusted to accomplish a desired disintegration time.
• disintegrants such as Ad-Di-Sol, Explotab, Pregelatinized starches, crospovidone NF and other materials known to the formulation art can be incorporated into the matrix as fine powder or beadlets.
• any sort of particle can be used in this formulation, so long as it contains or comprises one or more beneficial agents, is stable in the matrix-forming material during manufacturing and storage, and has sufficient size and definition in terms of shape and color so that it is visible in the matrix. Colored beadlets, as described below are most preferred.
• beneficial agent means any compound or material which acts on a mammal in one fashion or another when consumed for its intended use in the manner prescribed.
• a drug is a beneficial agent for the purposes of this definition.
• other compounds which can have a subjective or objective beneficial effect on the user and which are to be included within the meaning of this term.
• an antacid or anti-gas agent can have a beneficial effect when used to treat indigestion.
• a breath freshener provides an objective and a subjective beneficial effect to many people.
• Nutritional agents such as vitamins, minerals, or amino acid supplements are beneficial to those needing to supplement their diet. Flavors and sweeteners provide a subjective benefit and a source of energy as well, and are also included.
• Drugs and drug delivery are of greatest interest herein.
• the word "drug” is used in its broadest sense and includes any agent which exhibits a pharmacological effect on the user and which can be administered via SGC technology utilizing particles as described herein. Any solid or liquid form of a drug can be used provided it can be manufactured into a particulate, as is true for any compound which constitutes a beneficial agent for the purposes of this invention. Both fat soluble and water soluble drugs may be used. Drugs for treating cough, cold, and allergy symptoms are of most interest.
• Phenylpropanolamine hydrochloride, caramiphen edisylate, acetaminophen, aspirin or another non-steroidal anti-inflammatory, pseudoephrine hydrochloride, dextromethorphan hydrobromide, and chlorpheniramine maleate are most preferred.
• Beadlet size can vary in any given capsule. Preferred beadlets will have a diameter in the range of about 149 to 1190 microns. The most preferred particle size is between about 420 and 840 microns microns (about 20-40 mesh). Particle size can vary in a given preparation or particles of different narrow ranges can be confected and these final products mixed to provide a choice of preparations with different particle sizes.
• Particles can be comprised of pure agent or, as will more often be the case, the agent can be coated with a protective layer which may or may not affect how fast the particle dissolves and releases the active ingredient.
• Creating particles of pure agent is mostly a matter of shaping the raw material by some means, usually a mechanical means.
• a coating of some sort may be added to protect the neat compound. More often than not, one will want to coat the particles for both functional and aesthetic reasons.
• Pan coating for example, is a well established technology that provides a basic pellet.
• a more sophisticated approach is to create a core and then to add one or more layers of a coating to the core.
• any particles with different coating thicknesses are loaded into one capsule, drug can be delivered over an extended period to time.
• This technology was pioneered by R. H. Blythe in U.S. patent 2,738,303. He describes there a therapeutic preparation in unit dosage form prepared from non-pariel seeds (sugar pellets), screened, placed in a coating pan, wetted with syrup, then treated with a 80:20 mixture of dextro- amphetamine sulfate and calcium sulfate dihydrate, then dried.
• Particles can be prepared in a single color, or in different colors if desired. Dyes and lakes of any sort may be used so long as they are not toxic or do not have an untoward or deleterious effect on the user. For example blue particle could be prepared for use with a translucent white wax lozenge. Or red, white and blue beadlets could be incorporated into a sorbitol base to provide an aesthetically pleasing lozenge. Particle stability, as compared with stability of the active agent, is another factor which must be taken into consideration. Particles must remain chemically and physically stable under the conditions used to manufacture troches. Furthermore, particle and matrix must not undergo some kind of chemical or physical interaction once manufactured. It is not possible to identify or define all of the conditions or combinations which could lead to particle-matrix interactions. However, particulates coatings known to be soluble in sorbitol or corn syrup should not be used to formulate coated beads where such sugars are the intended matrix-forming agent.
• Stability of the beneficial agent is a consideration as well, just as it is with any formulation, not just these preparations. There is no single recipe for formulating a product which will not degrade chemically. Each formulation must be addressed on a case-by-case basis; this is within the skill of one trained in the formulation arts.
• Lozenges for example, are commonly manufactured by preparing a candy base by combining ingredients and cooking the mix, with or with out stirring, to create the stock from which the lozenge will be prepared. Then a portion of this mix which is held at an elevated temperature to keep it liquid is used as a diluent; particles are added to the liquid mix with stirring to create a dispersion. This material is poured into molds, cooled and packaged. Alternatively, products may be made by injection molding techniques. This approach is particularly useful where waxes are used as the matrix-forming agent. A heated mixture of wax and particles is passed through an injection molding apparatus in such as manner as to fill mold and allow for cooling of the product during the manufacturing cycle.
• a premixed stream of room temperature material is processed under pressure into molds to eliminate the need for a cooling step.
• a feed stock of matrix-forming material can be mixed with a feed-stock stream of particles, passed through a mixing device and injected into a mold to form the final product.
• Other injection molding processes are considered to be within the purview of this invention.
• Finished product may be packaged without any special handling precautions.
• the usual considerations such as the need to exclude moisture or ultraviolet light should be taken into consideration.
• the invention can be practiced within the context of packaging the product in opaque jar or overwrap.
• Any form or shape can be used in this invention.
• Troches or lozenges may be uniform in shape such as is the case for an oval, square, rectangular, or have multiple sided presentation.
• Geometric forms can be used. Shapes representing persons or things, either real or imagined can be prepared, especially when injection molding techniques are used. Shape and form are limited only by the imagination of the practitioner. The following examples are provided to illustrate the invention. They are not to be read as limiting the invention in any manner.
• Example 1 Preparation of Wax Matrix Caplets Containing Beadlets A required amount of white wax was taken into a glass beaker and heated in an oil bath until the wax melted using a hot plate. Beadlets obtained from Central Pharmaceuticals, Inc. Seymour, Indiana, were poured into the molten wax and stirred with a spatula to obtain a homogenous suspension. The molten wax/bead suspension was carefully poured into molds and allowed to cool and form hard caplets. These caplets were then pushed out of the molds.
• the active ingredients in the beadlets were chlorpheneramine maleate 12.0 mg and phenylpropanolamine HC175.0 mg. These beadlets were differentially coated so that some beadlets would release the actives immediately, and others would release their active ingredients at several time points over a 12 hour period.
• the active ingredients in the beadlets were chlorpheneramine maleate 12.0 mg and phenylpropanolamine HC175.0 mg. These beadlets were differentially coated so that some beadlets would release the actives immediately, and others would release their active ingredients at several time points over a 12 hour period.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Zoology (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Applications Claiming Priority (3)

Publications (2)

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Citations (4)

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• 1994
  • 1994-07-08 ZA ZA944949A patent/ZA944949B/xx unknown
  • 1994-07-12 CN CN94193367A patent/CN1130867A/zh active Pending
  • 1994-07-12 CZ CZ9666A patent/CZ6696A3/cs unknown
  • 1994-07-12 KR KR1019960700229A patent/KR960703572A/ko not_active Application Discontinuation
  • 1994-07-12 CA CA002167050A patent/CA2167050A1/en not_active Abandoned
  • 1994-07-12 NZ NZ269103A patent/NZ269103A/en unknown
  • 1994-07-12 PL PL94312503A patent/PL312503A1/xx unknown
  • 1994-07-12 HU HU9600048A patent/HUT73666A/hu unknown
  • 1994-07-12 SK SK33-96A patent/SK3396A3/sk unknown
  • 1994-07-12 EP EP94922131A patent/EP0785777A1/de not_active Withdrawn
  • 1994-07-12 WO PCT/US1994/007817 patent/WO1995002396A1/en not_active Application Discontinuation
  • 1994-07-12 AU AU72580/94A patent/AU684528B2/en not_active Ceased
  • 1994-07-12 JP JP7504669A patent/JPH09500135A/ja active Pending
• 1996
  • 1996-01-09 NO NO960098A patent/NO960098L/no not_active Application Discontinuation
  • 1996-01-11 FI FI960133A patent/FI960133A/fi unknown

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