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WO2000009171A1 - Produits contenant des agents biologiquement actifs, a gout desagreable, et leurs procedes de production - Google Patents

Produits contenant des agents biologiquement actifs, a gout desagreable, et leurs procedes de production Download PDF

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Publication number
WO2000009171A1
WO2000009171A1 PCT/US1999/017932 US9917932W WO0009171A1 WO 2000009171 A1 WO2000009171 A1 WO 2000009171A1 US 9917932 W US9917932 W US 9917932W WO 0009171 A1 WO0009171 A1 WO 0009171A1
Authority
WO
WIPO (PCT)
Prior art keywords
floss
ascorbic acid
particles
sucrose
xylitol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1999/017932
Other languages
English (en)
Inventor
Pradeepkumar P. Sanghvi
Madhusudan Hariharan
John R. Sisak
Tushar K. Misra
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biovail Technologies Ltd
Original Assignee
Fuisz Technologies Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fuisz Technologies Ltd filed Critical Fuisz Technologies Ltd
Priority to AU54700/99A priority Critical patent/AU5470099A/en
Publication of WO2000009171A1 publication Critical patent/WO2000009171A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/0012—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

  • the invention deals with fast-dissolving or easily chewable oral products containing unpleasant tasting, water-soluble bio-affecting agents, such as ascorbic acid (Vitamin C).
  • the products are comestible units made from compositions containing a blend of microparticles of the bio-affecting agents along with shearform floss particles. Methods of making the products are also described.
  • Ascorbic acid is exemplary of the generally water-soluble unpleasant-tasting, bio- affecting agents used herein.
  • Ascorbic acid a water-soluble vitamin, is used in the prevention or treatment of scurvy, anemia, gum infections, dental caries, and other ailments.
  • doses of 30 mg to 60 mg per day for children and 60 mg per day for adults are recommended.
  • Ascorbic acid is readily absorbed into the body.
  • oral products for administering ascorbic acid have drawbacks. Among these drawbacks is the acid's astringent taste, which tends to lower patient compliance with recommended dosage levels.
  • Most products on the market do not dissolve quickly in the mouth's saliva, requiring vigorous chewing or taking the products with water. Such products can stay in the mouth for significant periods of time, resulting in exposure to the undesirable taste of any unpleasant tasting bio-affecting agents therein for significant periods of time.
  • Comestible units for the oral delivery of water-soluble, unpleasant-tasting active agents are made from a composition containing the following components:
  • saccharide-based shearform floss particles (b) saccharide-based shearform floss particles; and (c) suitable excipients selected from lubricants, flavor enhancers, glidants, fillers and colorants.
  • suitable excipients selected from lubricants, flavor enhancers, glidants, fillers and colorants.
  • the method of making these units comprises combining and shaping components (a)-(c), as follows:
  • step (3) blending the product of step (2) with microparticles containing unpleasant tasting bio-affecting agent(s) and excipients, and
  • compositions and methods of the invention generally dissolve in the consumer's mouth instantaneously, i.e., in 10 seconds or less, based on organoleptic testing, without the need for chewing or drinking water.
  • the saliva in the mouth provides sufficient liquid to cause quick dissolution.
  • fast- dissolving units assures that the water-soluble vitamin or other unpleasant tasting bio- affecting agent(s) spend a minimal amount of time in the mouth, so that their unpleasant taste is barely detected and patient compliance improves.
  • the comestible units made using the compositions and methods of the invention generally dissolve in the consumer's mouth upon gentle chewing, (i.e., in 10 seconds or less, based on organoleptic testing, without the need for drinking water). Also, the optional presence of one or more coatings on the microparticles of agent(s) and the pleasant flavor of the floss and other excipients tends to make any unpleasant taste less noticeable.
  • the invention relates to novel comestible units and the method of making them.
  • compositions from which the units are made have three principal components: (a) coated or uncoated microparticles of bio-affecting agents,
  • the coatings on the microparticles provide improved stability, taste- masking, or both.
  • the bio-affecting agents used in the invention include unpleasant tasting water- soluble vitamins or other water-soluble active agents, i.e., agents having biological activity. Suitable agents include: ascorbic acid, ferrous fumarate, folic acid, niacinamide, pyridoxine hydrochloride, riboflavin, thiamine mononitrate, Vitamin A acetate, Vitamin B 12 , Vitamin D (e.g., Vitamin D 3 ) and Vitamin E and its acetate. Ascorbic acid and
  • Vitamin D along with pharmaceutically acceptable derivatives of same and combinations with other bio-affecting agents, e.g., Vitamin D with calcium carbonate, are preferred.
  • the microparticles used in the invention are generally particles of about 0.1 to about 600 microns in size. They need not be coated.
  • the microparticles preferably have one or more coating layers, with each layer containing one or more materials selected from: mono- and diglycerides; starch; or cellulose derivatives, e.g., ethyl cellulose.
  • Other coating materials which impart taste- masking, improved stability, or other properties can be used.
  • Coated microparticles generally contain from about 50% to about 100%, preferably about 60%, of active agent(s), with the remainder being one or more coating(s).
  • Preferred coated ascorbic acid particles include "DESCOTE ASCORBIC ACID 60%" sold by Particle Dynamics of St. Louis, MO.
  • Useful ascorbic acid particles may have no coatings, i.e., be 100% acid. These include "Ascorbic Acid USP 100%" from BASF, Mt. Olive, NJ. The particles may have low coating levels, such as those bearing about 2% to 4%, preferably 2.5%, ethyl cellulose coatings. The product sold as Ascorbic Acid 97.5% by Roche Vitamins of Paramus, NJ is useful.
  • the particles may be granulated with starch and lactose.
  • the product sold as Ascorbic acid 90% C-90 by Roche Vitamins of Paramus, NJ is useful.
  • Spherical microparticles, e.g., microspheres, are useful in the invention. However, they are not required. Accordingly, suitably sized microparticles having irregular and/or non-spherical shapes can be used.
  • Useful shearform floss particles are particles described in U. S. Applications SN 08/915,067 and SN 08/915,068, both filed August 20, 1997, and assigned to Fuisz Technologies Ltd.
  • Preferred flosses are termed "unifloss" particles. They contain one or more saccharides and two or more sugar alcohols. Suitable particles are made from compositions containing about 80% to 85% sucrose, about 5% to 20% sorbitol, about 5% to 25% xylitol, and about 0 to 10% polyoxyethylene sorbitan fatty acid esters (e.g., TWEEN 80).
  • Suitable particles are made from compositions containing about 80% to 85% sucrose, about 5% to 20% sorbitol, about 5% to 25% xylitol, and about 0 to 10% polyoxyethylene sorbitan fatty acid esters (e.g., TWEEN 80).
  • floss constituents may be used as floss constituents.
  • the floss particles dissolve very quickly in the mouth, releasing the sweeteners therein almost instantaneously.
  • the flosses are made by subjecting blends of sugar(s) and sugar alcohol(s) to flash flow processing in a suitable spinning device, such as that described in U. S. Patent Application Serial No. 08/854,344, filed May 12, 1997.
  • the spun floss is chopped for about 0.5 to about 5 minutes, preferably about 1 to 2 minutes, in the presence of 0% to about 2%, preferably about 2%, lactose, using a Littleford Mixer or other suitable mixing/grinding device.
  • the chopped floss particles generally range in size from about 1 to about 1 ,000 microns.
  • the floss is contacted with about 0.1% to about 10% ethanol or other suitable crystallization enhancer(s).
  • ethanol is used in amounts ranging from about 0.5% to about 5.0%.
  • the floss is then treated to remove excess ethanol.
  • crystallization enhancers include surfacants, such as Tween 80, which are used at concentration levels of about 0.001% to about 1.00%.
  • excipients conventionally used in comestible units, especially those employed in food and pharmaceutical formulations, can be employed in the invention. They include lubricants, flavors, flavor enhancers (e.g., sweeteners), glidants, fillers, colorants, perfumes and the like.
  • Lubricants are generally employed in amounts of about 0.05% to about 5.0%, with 0.3% to about 0.8% preferred.
  • Adipic acid a preferred lubricant, also functions as a flavor enhancer and a salivation enhancer.
  • Another preferred lubricant is sodium stearyl fumarate.
  • Magnesium stearate is a preferred lubricant for the chewable comestible units. It is preferred that the lubricant particles be milled to #200 mesh size before they are added.
  • Flavor enhancers are present in amounts of about 1% to about 10%.
  • Typical flavor enhancers include sweeteners, e.g., mannitol, monoammonium glycyrrhizinate (MAGNASWEET 100 of Mafco Worldwide Corp., Camden, NJ) and the like. Mixtures can be used.
  • Flavors include those that are perceived as orange, lemon, fruit punch, or whipped cream flavors and the like. Mixtures can be used.
  • Glidants such as fumed silica (e.g. , S YLOID 244FP) or talc, are generally used at levels of about 0.05% to about 2.0%.
  • the comestible units of the invention are made by mixing the microparticles, the floss, and the excipients, then shaping the mix, e.g., via compression, into comestible units, preferably tablets.
  • the overall process involves:
  • microparticles are coated, using conventional coating techniques prior to step (2).
  • the floss particles are prepared using procedures described in U. S. Patent Application Serial No. 08/915,068, filed August 20, 1997.
  • a mixture of sucrose, sugar alcohols and TWEEN 80 is prepared and spun into a floss at about 3,500 to 4,000 rpm (50 to 60 Hz) using a suitable spinning device.
  • the floss was chopped in a higher shear mixer/chopper for about 0.5 to 2.0 minutes.
  • ethanol or another crystallization enhancer
  • ethanol or another crystallization enhancer
  • spraying or other suitable methods to initiate crystallization.
  • the floss is treated to remove excess enhancer and is optionally milled or screened. It is then used in making tablets or other comestible units.
  • the ingredients are typically blended in a Littleford Mixer. They are mixed at speeds of about 60 to about 140 rpm for about 5 to about 15 minutes. Alternatively, the ingredients may be mixed with a V-blender or other suitable mixing device.
  • the blends are tableted using a standard pharmaceutical tablet press, e.g., a Kilian T-200 tablet press. Tablets are made to thicknesses of about 3 to about 8 millimeters, with 4.5 to 5.5 millimeters preferred.
  • the fast dissolving tablets are compressed to hardnesses of about 0.5 to about 6.0 pounds, with about 1.0 to about 3.0 pounds preferred.
  • the chewable tablets are compressed to hardnesses of about 6.0 pounds to 20.0 pounds, with about 10.0 to about 12.0 pounds preferred.
  • compositions and methods of the invention can also be used to make other comestible units. It is preferred that the units be orally ingestible, e.g., tablets, lozenges, and the like.
  • EXAMPLES The following examples illustrate the invention.
  • Example 1 A floss containing 78.25% sucrose, 11.00% sorbitol, 10.0% xylitol and 0.75% Tween 80 was prepared as follows:
  • the mix of ingredients (2 kg) was spun into floss at 3600 rpm (60Hz) using a 5" spinning head in the device described in U. S. Serial No. 08/854,344, filed May 12, 1997.
  • the floss was chopped in a high shear mixer/chopper for 2 minutes.
  • the chopped floss was treated with 0.5% ethanol and allowed to dry for 90 minutes.
  • TOTAL 100.00 The ingredients were mixed in a Littleford Mixer for 10 to 15 minutes. The mix was tableted on a Kilian T-200 press to yield 0.65g tablets of 2 pounds hardness, and 3.06% moisture content, having thicknesses of 4.5mm to 5.5mm.
  • Example 2 Using the floss particles and the general procedure of Example 1, 250mg tablets of ascorbic acid, weighing 1 gram each, were made from the following formulation:
  • the floss was prepared and chopped using the general procedure of Example 1.
  • the chopped floss was treated with 4.0% ethanol and allowed to dry for 90 minutes.
  • the 4.0% ethanol-treated floss particles were then used in the following formulation.
  • a chewable calcium carbonate/vitamin D combination product was made as follows:
  • sucrose, sorbitol, xylitol, and Polysorbate 80 were blended in a Littleford FKM600 mixer for 10 minutes. The blend was then subjected to Shearform processes at 60Hz and 250°C temperature using the 5" Pharma processing head. The floss manufactured was chopped in the Littleford FKM600 mixer with 2% lactose and treated with ethanol (7% of the floss). The floss was dried at 45°C for 150 minutes, the floss was then milled/sieved through a 20mesh screen using a Fitzmill or Apexmill.
  • Vitamin D3 0.16%
  • the calcium carbonate was blended with vitamin D3 for 15 minutes at speed 1 in a Diosna 600.
  • the milled floss was added and blended further for 10 minutes.
  • the flavors and flow agent were added and blend for additional 7 minutes.
  • the blend was compressed on a rotary tablet press at 85N hardness, 2.75g tablet weight, 19mm concave round or 19mm flat-faced radial edge tooling.
  • the floss was prepared and chopped using the general procedure of Example 1.
  • the chopped floss was treated 7.0% ethanol and allowed to dry for 150 minutes at 45°C.
  • the 7.0% ehanol treated floss was then used in the following formulation.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (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)

Abstract

L'invention concerne de nouvelles unités comestibles se dissolvant rapidement, par exemple des comprimés, produites à partir de compositions renfermant des agents solubles dans l'eau, à goût désagréable, ainsi que des particules matricielles cisaillées à base de saccharide, et des excipients.
PCT/US1999/017932 1998-08-12 1999-08-10 Produits contenant des agents biologiquement actifs, a gout desagreable, et leurs procedes de production Ceased WO2000009171A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU54700/99A AU5470099A (en) 1998-08-12 1999-08-10 Products containing unpleasant tasting bio-affecting agents and methods of making them

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13298398A 1998-08-12 1998-08-12
US09/132,983 1998-08-12

Publications (1)

Publication Number Publication Date
WO2000009171A1 true WO2000009171A1 (fr) 2000-02-24

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ID=22456497

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/017932 Ceased WO2000009171A1 (fr) 1998-08-12 1999-08-10 Produits contenant des agents biologiquement actifs, a gout desagreable, et leurs procedes de production

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AU (1) AU5470099A (fr)
WO (1) WO2000009171A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002058735A1 (fr) * 2001-01-25 2002-08-01 Gainful Plan Limited Procede de preparation de materiaux biologiques et produits resultants
US9101625B2 (en) 2006-08-30 2015-08-11 Purdue Pharma L.P. Buprenorphine-wafer for drug substitution therapy
DE202015004009U1 (de) 2015-06-09 2016-01-11 Hermes Arzneimittel Gmbh Schnell zerfallende Tabletten ohne Zerfallsbeschleuniger
DE202016005032U1 (de) 2016-08-19 2017-02-10 Hermes Arzneimittel Gmbh Schnell zerfallende Efeu-Trinktabletten ohne Zerfallsbeschleuniger

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999008658A1 (fr) * 1997-08-20 1999-02-25 Fuisz Technologies Ltd. Unites de prise comestibles se dissolvant rapidement, formees dans des conditions de vitesse elevee/pression elevee

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999008658A1 (fr) * 1997-08-20 1999-02-25 Fuisz Technologies Ltd. Unites de prise comestibles se dissolvant rapidement, formees dans des conditions de vitesse elevee/pression elevee

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002058735A1 (fr) * 2001-01-25 2002-08-01 Gainful Plan Limited Procede de preparation de materiaux biologiques et produits resultants
US9101625B2 (en) 2006-08-30 2015-08-11 Purdue Pharma L.P. Buprenorphine-wafer for drug substitution therapy
US9370512B2 (en) 2006-08-30 2016-06-21 Purdue Pharma L.P. Buprenorphine-wafer for drug substitution therapy
US9763931B2 (en) 2006-08-30 2017-09-19 Purdue Pharma L.P. Buprenorphine-wafer for drug substitution therapy
US9861628B2 (en) 2006-08-30 2018-01-09 Rhodes Pharmaceuticals L.P. Buprenorphine-wafer for drug substitution therapy
DE202015004009U1 (de) 2015-06-09 2016-01-11 Hermes Arzneimittel Gmbh Schnell zerfallende Tabletten ohne Zerfallsbeschleuniger
DE202016005032U1 (de) 2016-08-19 2017-02-10 Hermes Arzneimittel Gmbh Schnell zerfallende Efeu-Trinktabletten ohne Zerfallsbeschleuniger

Also Published As

Publication number Publication date
AU5470099A (en) 2000-03-06

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