US2990328A - Stable therapeutic compositions containing acetylsalicylic acid-anhydride - Google Patents

Stable therapeutic compositions containing acetylsalicylic acid-anhydride Download PDF

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Publication number
US2990328A
US2990328A US729258A US72925858A US2990328A US 2990328 A US2990328 A US 2990328A US 729258 A US729258 A US 729258A US 72925858 A US72925858 A US 72925858A US 2990328 A US2990328 A US 2990328A
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Prior art keywords
anhydride
acid
milligrams
acetylsalicylic
asa
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Expired - Lifetime
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US729258A
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English (en)
Inventor
Edward H Lincoln
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Pharmacia and Upjohn Co
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Upjohn Co
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Publication date
Priority to NL121097D priority Critical patent/NL121097C/xx
Priority to BE585778D priority patent/BE585778A/xx
Priority to NL245245D priority patent/NL245245A/xx
Application filed by Upjohn Co filed Critical Upjohn Co
Priority to US729258A priority patent/US2990328A/en
Priority to GB9597/59A priority patent/GB885081A/en
Application granted granted Critical
Publication of US2990328A publication Critical patent/US2990328A/en
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Expired - Lifetime legal-status Critical Current

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Classifications

    • 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
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame

Definitions

  • Acetylsalicylic acid is known to decompose to the irritating compounds
  • acetic and salicylic acids are known to be an irritant to the gastric mucosa.
  • An additional object is to provide such compositions which do not form irritating amounts of acetic and salicylic acids in the stomach after oral administration.
  • a further object is to provide such compositions which are free from mucosal irritation side-effects.
  • a still further object is to provide such compositions which are stable under manufacturing and storage conditions.
  • 'Ilheterm" dosage unit form refers to physically discrete units suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of active material calculated to produ ce the desired therapeutic effect in association with the required pharmaceutical diluent or carrier.
  • the specificationsfor the novel dosage unit forms of this invention are dictated by and directly dependent upon (a) the unique characteristics of the active material and the particulartherapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for therapeutic use in human beings, as disclosed in detail in this specification, being features of the present invention.
  • suitable solid oral dosage unit forms in accord with this invention are a tablet, a capsule, a pill, a powder packet, an effervescent granule, a pilule, a Water, a chewing gum, a cachet, a pellet, multiples of any of the foregoing, when segregated as a single dose.
  • forms known as the sustained-release, delayed action or enteric types are included.
  • the basic method of preparing, the desired dosage unit form comprises mixing the active ingredient [acetylsalh cylic acid] anhydride with an appropriate diluent including. an appropriate acidic substance and preparing the dosage unit form by methods and with means known in the 'art.
  • nonalkaline is intended to mean neutral and acidic.
  • Other than'neutral and acidic, i.e., alkaline conditions have been found to hasten deterioration of the active ingredient, [acetylsalicylic acidJ-anhydride.
  • alkaline conditions have been found to hasten deterioration of the active ingredient, [acetylsalicylic acidJ-anhydride.
  • alkaline conditions have been found to hasten deterioration of the active ingredient, [acetylsalicylic acidJ-anhydride.
  • alkaline deterioration is more pronounced at temperatures above 25 degrees centigrade.
  • the experimental data show that the presence of water is a problem both in the bulk mixtures used for manufacturing and in the final dosage unit forms. While deterionation from the presence of water is not immediately ittsm b e i s e u i fa ms h t ees c grade, the data at temperatures above 25 degrees centigrade indicate that long-term stability at 25 degrees centigrade and short-term stability at temperatures above 25 degrees centigrade would be unsatisfactory. Thus, for long-term stability at 25 degrees centigradeand shortterm stability above 25 degrees centigrade, substantially anhydrous dosage unit forms are preferred.
  • diluen is used in reference to pharmaceutically acceptable carriers, bulking agents, excipients, binders, lubricants, adhesives, disintegrators, stabilizers (e.g., acidic substances infraland the like, for example: starch, talc, sucrose, dicalcium phosphate, lactose, sorbitol, 'mannitol, Thixcin (ajhighly saturated castor oil), mixtures of the foregoing, andthe. like.
  • pharmaceutically acceptable carriers bulking agents, excipients, binders, lubricants, adhesives, disintegrators, stabilizers (e.g., acidic substances infraland the like, for example: starch, talc, sucrose, dicalcium phosphate, lactose, sorbitol, 'mannitol, Thixcin (ajhighly saturated castor oil), mixtures of the foregoing, andthe. like.
  • acidic substances for. example: citric acid; ascorbic, acid, alkali metal bitartrates, alkali metal biphosphates, tartaric acid, malic acid, glutamic acid hydrochloride, pyridoxine hydrochloride, nicotinic acid, acidic amino acids, salts of amino acids, succinic acid, glucuronic acid, glutaric acid, pimelic acid, malonic acid, mandelic acid, adipic acid, tricarballylie acid, mixtures of the foregoing, and the like, From among this, group sodium biphosphate, citric acid, pyridoxine hydrochloride, tartaric acid and malic acid are preferred.
  • the amount of [acetylsalicyclio acidl-anhydride can be varied over a considerable range. From about 25 milligrams to about 1000 milligrams per dosage unit form can be utilized, with from about sixty milligrams to about 400 milligrams preferred. The smaller amounts are preferred in the dosage unit forms for children. The higher dosages are most useful in the rheumatic type diseases.
  • compositions of this invention can be added to the compositions of this invention.
  • active ingredients are the following: acetophenetidin, caifeine, codeine and its salts, salicylamide, N-acetyl-para-aminophenol, anti-inflammatory steroids, for example, cortisone, hydrocortisone, 6-methyl-delta-1- hydrocortisone, prednisone, prednisolone, their esters and the salts of acid esters thereof, and like derivatives.
  • ditional illustrative examples are the following: tranquilizers, antihistaminics, antitussive agents, antibiotics, sedatives and vitamins.
  • compositions of this invention possess analgesic
  • antipyretic and antirheumatic properties are useful in therelated afilictions and disorders susceptible to such properties.
  • ASA acetylsalicylic acid. sterotex hydrogenated vegetable 011.
  • ASA acetylsalicylic acid
  • ASA acetylsalicy1ic acid
  • Table V contains the data on stability ofrnixtures consisting of [acetylsalicyclic acidl anhydrideand various acidic substances and stored in soft glass" containers. The mixtures were prepared by gr-anulating thirty grams ofscrew caps.
  • the data in Table V show the superior stability of 8
  • the granulation is prepared bymixing the [acetylsalicyliclzanhydridewith the sorbi'toli-starch paste, which contains the citric acid dissolved in the water, and drying the mixture, at about 120 degrees Fahrenheit for ten to a twenty hours. After'milling and screening, the granulation is mixedithoroughly with the starch-talc lubricant and-compressedinto tablets. Clinical testing shows that these tablets, each containing 300 milligrams of [acetylsalicylic acid]-anhydride, do not causegastric irritation and provide superior blood levels of salicylate including the esterified compound, acetylsalicylic acid.
  • an anti-inflammatory steriod for example, 6-methyl-prednisolone, about 0.15 to about 4 milligrams; cortisone acetate, about 2.5 to about milligrams; hydrocortisone acetate, about 2 to about 20'mi1ligrams; prednisone, about 0.25 to about 5 milligrams; 6-fluoro-hydrocortisone, about 0.15 to about 4 milligrams; 6-fluoro-prednisolone,. about 0.15 to about 4 milligrams; gives a composition useful in arthritic affiictions.
  • tablets containing 60, 160, 400, 600 and 1000 milligrams of [-acetylsalicylic acidl-anhydride can be prepared through substituting the 7500 grams of the a.n-.
  • Table VI contains the data on stability of mixtures consisting of [acetylsalicyclic acid] -anhydride and various amounts of citric acid. The mixtures were prepared as in Table V. i
  • the illustrative example contains citric acid, one of the five preferred acidic substances the others being malic acid, pyridoxine hydrochloride, sodium biphosphate and tartaric acid.
  • the preferred amount of said acidic substances is from about one to about fifty milligrams per 300 milligrams of [-acetylsalicyclic acidl-anhydride.
  • tarqhiho isd e "-9-"? 403.
  • Eight to ten successive coatings are applied to give a gum containing fifty milligrams of acetylsalicylic acid] -anhydride.
  • a second dusting with the hydrogenated castor oil is applied.
  • the final finishing and protective coatings contain flavor, coloring and polishing ingredients. It is preferred to apply a final water-proof-preservative type of coating, for example, carnauba Wax.
  • Each packet contains:
  • EXAMPLE Hard-filled capsule Following the procedure of Example 2, capsules are prepared containing 228 milligrams of [acetylsalicylic acidJ-anhydride from 70 to 160 milligrams of acetophenetidin and from sixteen to 35 milligrams of cafieine per capsule.
  • EXAMPLE 6 Compressed tablet Following the procedure of Example 1, tablets are prepared with a complementary active ingredient by adding to 30 milligrams of codeine sulfate per 300 milligrams of [acetylsalicylic acid]-anhydride, granulating and compressing by the method shown.
  • EXAMPLE 9 Hard-filled capsule Following the procedure of Example 2, capsules are prepared with a complementary active ingredient by adding 1 to 4 milligrams of chlorpheniramine maleate per capsule.
  • Milligrams [Acetylsalicylic acidJ-anhydride 300 6-methyl prednisolnne 1 Citric acid 10 Ascorbic acid, ten milligrams per tablet, can be added to the above formula.
  • a stable, solid oral therapeutic preparation in dosage unit form comprising [acetylsalicylic acid] -anhydride and apharmaceutically acceptable non-alkaline diluentcontaining from about 0.3 to about 17% by weight ofsaid anyhdride of a pharmaceutically-acceptable acid-reacting stabilizing compound to stabilize the preparation against decomposition by alkali, which diluent does not lower substantially the melting point of said anhydride.
  • a substantially anhydrous, stable, solid oral therapeutic preparation in dosage unit form comprising [acetylsalicylic acid]-anhydride and a pharmaceutically acceptable non-alkaline diluent containing from about 0.3 to about 17% by weight of said anhydride of a pharmaceutically-acceptable acid-reacting stabilizing compound to stabilize the preparation against decomposition by alkali, which diluent does not lower substantially the melting point of said anhydride.
  • a stable, solid oral therapeutic preparation in dosage unit form comprising from about 25 to about 1000 milligrams of [acetylsalicylic acidJ-anhydride and a pharmaceutically acceptable non-alkaline diluent containing from about 0.3 to about 17% by weight of said anhydride of a pharmaceutically-acceptable acid-reacting stabilizing compound to stabilize the preparation against decomposition by alkali, which diluent does not lower substantially the melting point of said anhydride.
  • a substantially anhydrous, stable, solid oral therapeutic preparation in dosage unit form comprising from about sixty to about 400 milligrams of [acetylsalicylic acidJ-anhydride and a pharmaceutically acceptable istlkaline diluent containing from about 0.3 to about 17% by weight of said anhydride of a pharmaceutically-acceptable acid-reacting stabilizing compound to stabilize the preparation against decomposition by alkali, which diluent does not lower substantially the melting point of said anhydride.
  • a substantially anhydrous, stable solid oral therapeutic preparation in dosage unit form comprising an antiinflammatory steroid, from about sixty to about 400 milligrams of [acetylsalicylic acid]-anl1ydride and a pharmaceutically acceptable non-alkaline diluent containing from about 0.3 to about 17% by weight of said anhydride of a pharmaceutically-acceptable acid-reacting stabilizing compound to stabilize the preparation against decomposition by alkali, which diluent does not lower substantially the melting point of said anhydride.
  • a substantially anhydrous stable, oral therapeutic tablet comprising from about 0.15 to about four milligrams of 6-methylprednisolone, from about sixty to about 400 milligrams of [acetylsalicylic acid] -anhydride and a pharmaceutically acceptable non-alkaline diluent containing from about 0.3 to about 17% by weight of said anhydride of a pharmaceutically-acceptable acid-reacting stabilizing compound to stabilize the preparation against decomposition by alkali, which diluent does not lower substantially the melting point of said anhydride.
  • a substantially anhydrous stable, oral therapeutic tablet comprising one milligram of -methylprednisolone, 300 milligrams of [acetylsalicylic acid]-anhydride and a pharmaceutically acceptable non-alkaline diluent containing from about 0.3 to about 17% by weight of said anhydride of a pharmaceutically-acceptable acid-reacting stabilizing compound to stabilize the preparation against decomposition by alkali, which diluent does not lower substantially the melting point of said anhydride.
  • a stable, solid oral therapeutic preparation in dosage unit form comprising [acetylsalicylic acid] -anhydride and a pharmaceutically acceptable non-alkaline diluent containing from about 0.3 to about 17% by weight of said anhydride of an acid-reacting substance selected from the group consisting of citric acid, ascorbic acid, alkali metal bitartrates, alkali metal biphosphates, tartaric acid, malic acid, glutamic acid hydrochloride, pyridoxine hydrochloride, nicotinic acid, acidic amino acids, salts of amino acids, succinic acid, glucuronic acid, glutaric acid, pimelic acid, malonic acid, mandelic acid, adipic acid, tri- CatballYliCf acid, and mixtures "(.hereof',which diluent dbes notzlower i 'substnti'allythea melting point ofsaid aphy dri iei;

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US729258A 1958-04-18 1958-04-18 Stable therapeutic compositions containing acetylsalicylic acid-anhydride Expired - Lifetime US2990328A (en)

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Application Number Priority Date Filing Date Title
NL121097D NL121097C (enrdf_load_stackoverflow) 1958-04-18
BE585778D BE585778A (enrdf_load_stackoverflow) 1958-04-18
NL245245D NL245245A (enrdf_load_stackoverflow) 1958-04-18
US729258A US2990328A (en) 1958-04-18 1958-04-18 Stable therapeutic compositions containing acetylsalicylic acid-anhydride
GB9597/59A GB885081A (en) 1958-04-18 1959-03-19 Improvements in or relating to therapeutic compositions containing (acetylsalicylic acid)-anhydride

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Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3495001A (en) * 1968-05-27 1970-02-10 Miles Lab Effervescent compositions of acetylsalicylic acid
US4028239A (en) * 1973-06-03 1977-06-07 Lonza Ltd. Process for preventing lime deposits in a humidifier
US4294819A (en) * 1980-08-18 1981-10-13 Bristol-Myers Company Alkaline analgesic capsule
US4339428A (en) * 1980-08-18 1982-07-13 Bristol-Myers Company Capsule product containing high dosage of aspirin in powder or granulated form and alkaline tablet or pellet comprising magnesium carbonate, calcium carbonate and a magnesium dry component
EP0045238A3 (en) * 1980-07-29 1983-02-16 Sanofi, Societe Anonyme Acid stabilized compositions of thieno-pyridine derived compounds and process for preventing degradation of such compounds
US4900559A (en) * 1985-12-12 1990-02-13 Briston-Myers Company Stabilized enteric coated aspirin granules and process of preparation
WO2001049124A1 (en) * 1999-12-30 2001-07-12 Wm. Wrigley Jr. Company Release of lipophilic active agents from chewing gum
US6290985B2 (en) 1999-04-06 2001-09-18 Wm. Wrigley, Jr. Company Over-coated chewing gum formulations including tableted center
US6350480B1 (en) * 1999-12-30 2002-02-26 Wm. Wrigley Jr. Company Chewing gum product including a hydrophilic gum base and method of producing
US6355265B1 (en) 1999-04-06 2002-03-12 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US6444241B1 (en) 2000-08-30 2002-09-03 Wm. Wrigley Jr. Company Caffeine coated chewing gum product and process of making
US20020159956A1 (en) * 1999-04-06 2002-10-31 Ream Ronald L. Over-coated chewing gum formulations
US20020164398A1 (en) * 1998-12-15 2002-11-07 Johnson Sonya S. Method and product for accelerating absorption of medicaments through oral mucosa
US6531114B1 (en) 1999-04-06 2003-03-11 Wm. Wrigley Jr. Company Sildenafil citrate chewing gum formulations and methods of using the same
US6541048B2 (en) 1999-09-02 2003-04-01 Wm. Wrigley Jr. Company Coated chewing gum products containing an acid blocker and process of preparing
US6569472B1 (en) 2000-09-01 2003-05-27 Wm. Wrigley Jr. Company Coated chewing gum products containing antacid and method of making
US6572900B1 (en) 2000-06-09 2003-06-03 Wm. Wrigley, Jr. Company Method for making coated chewing gum products including a high-intensity sweetener
US6579545B2 (en) 2000-12-22 2003-06-17 Wm. Wrigley Jr. Company Coated chewing gum products containing an antigas agent
US6586023B1 (en) 1998-12-15 2003-07-01 Wm. Wrigley Jr. Company Process for controlling release of active agents from a chewing gum coating and product thereof
US6627234B1 (en) 1998-12-15 2003-09-30 Wm. Wrigley Jr. Company Method of producing active agent coated chewing gum products
US6645535B2 (en) 1999-09-02 2003-11-11 Wm. Wrigley Jr. Company Method of making coated chewing gum products containing various antacids
US6663849B1 (en) 2000-09-01 2003-12-16 Wm. Wrigley Jr. Company Antacid chewing gum products coated with high viscosity materials
US6773716B2 (en) 1999-04-06 2004-08-10 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US20040185144A1 (en) * 2000-06-09 2004-09-23 Witkewitz David L. Method for making coated chewing gum products with a coating including an aldehyde flavor and a dipeptide sweetener
US6949264B1 (en) 1996-11-27 2005-09-27 Wm. Wrigley Jr. Company Nutraceuticals or nutritional supplements and method of making
US20060141008A1 (en) * 1999-04-06 2006-06-29 Ream Ronald L Over-coated product including consumable center and medicament
US20100104620A1 (en) * 1999-04-06 2010-04-29 Wm. Wrigley Jr. Company Over-coated product including tableted center and medicament
US8679522B2 (en) 1999-09-20 2014-03-25 Jack Barreca Chewing gum
US9253991B2 (en) 1999-09-20 2016-02-09 Jack Barreca Chewing gum with B vitamins
US9387168B2 (en) 1999-09-20 2016-07-12 Jack Barreca Chewing gum with tomatidine
US20190350946A1 (en) * 2017-08-04 2019-11-21 Poli Md S.R.L. Medical Device for the Treatment of HPV Cutaneous Infections

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US922766A (en) * 1907-10-31 1909-05-25 Farbenfab Vorm Bayer F & Co Anhydrid of acyl salicylic acid.
US2888382A (en) * 1957-10-28 1959-05-26 Upjohn Co Therapeutic composition and process

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US922766A (en) * 1907-10-31 1909-05-25 Farbenfab Vorm Bayer F & Co Anhydrid of acyl salicylic acid.
US2888382A (en) * 1957-10-28 1959-05-26 Upjohn Co Therapeutic composition and process

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3495001A (en) * 1968-05-27 1970-02-10 Miles Lab Effervescent compositions of acetylsalicylic acid
US4028239A (en) * 1973-06-03 1977-06-07 Lonza Ltd. Process for preventing lime deposits in a humidifier
EP0045238A3 (en) * 1980-07-29 1983-02-16 Sanofi, Societe Anonyme Acid stabilized compositions of thieno-pyridine derived compounds and process for preventing degradation of such compounds
US4294819A (en) * 1980-08-18 1981-10-13 Bristol-Myers Company Alkaline analgesic capsule
US4339428A (en) * 1980-08-18 1982-07-13 Bristol-Myers Company Capsule product containing high dosage of aspirin in powder or granulated form and alkaline tablet or pellet comprising magnesium carbonate, calcium carbonate and a magnesium dry component
US4900559A (en) * 1985-12-12 1990-02-13 Briston-Myers Company Stabilized enteric coated aspirin granules and process of preparation
US6949264B1 (en) 1996-11-27 2005-09-27 Wm. Wrigley Jr. Company Nutraceuticals or nutritional supplements and method of making
US6586023B1 (en) 1998-12-15 2003-07-01 Wm. Wrigley Jr. Company Process for controlling release of active agents from a chewing gum coating and product thereof
US20020164398A1 (en) * 1998-12-15 2002-11-07 Johnson Sonya S. Method and product for accelerating absorption of medicaments through oral mucosa
US6627234B1 (en) 1998-12-15 2003-09-30 Wm. Wrigley Jr. Company Method of producing active agent coated chewing gum products
US6592850B2 (en) 1998-12-15 2003-07-15 Wm. Wrigley Jr. Company Sildenafil citrate chewing gum formulations and methods of using the same
US7163705B2 (en) 1998-12-15 2007-01-16 Wm. Wrigley Jr. Company Coated chewing gum product and method of making
US20020159956A1 (en) * 1999-04-06 2002-10-31 Ream Ronald L. Over-coated chewing gum formulations
US20100104620A1 (en) * 1999-04-06 2010-04-29 Wm. Wrigley Jr. Company Over-coated product including tableted center and medicament
US6465003B2 (en) 1999-04-06 2002-10-15 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US6531114B1 (en) 1999-04-06 2003-03-11 Wm. Wrigley Jr. Company Sildenafil citrate chewing gum formulations and methods of using the same
US20060141008A1 (en) * 1999-04-06 2006-06-29 Ream Ronald L Over-coated product including consumable center and medicament
US6558692B2 (en) 1999-04-06 2003-05-06 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US6290985B2 (en) 1999-04-06 2001-09-18 Wm. Wrigley, Jr. Company Over-coated chewing gum formulations including tableted center
US6773716B2 (en) 1999-04-06 2004-08-10 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US7935362B2 (en) 1999-04-06 2011-05-03 Wm. Wrigley Jr. Company Over-coated product including consumable center and medicament
US6322806B1 (en) 1999-04-06 2001-11-27 Wm. Wrigley Jr. Company Over-coated chewing gum formulations including tableted center
US6355265B1 (en) 1999-04-06 2002-03-12 Wm. Wrigley Jr. Company Over-coated chewing gum formulations
US6645535B2 (en) 1999-09-02 2003-11-11 Wm. Wrigley Jr. Company Method of making coated chewing gum products containing various antacids
US6541048B2 (en) 1999-09-02 2003-04-01 Wm. Wrigley Jr. Company Coated chewing gum products containing an acid blocker and process of preparing
US9387168B2 (en) 1999-09-20 2016-07-12 Jack Barreca Chewing gum with tomatidine
US8679522B2 (en) 1999-09-20 2014-03-25 Jack Barreca Chewing gum
US9253991B2 (en) 1999-09-20 2016-02-09 Jack Barreca Chewing gum with B vitamins
US6350480B1 (en) * 1999-12-30 2002-02-26 Wm. Wrigley Jr. Company Chewing gum product including a hydrophilic gum base and method of producing
WO2001049124A1 (en) * 1999-12-30 2001-07-12 Wm. Wrigley Jr. Company Release of lipophilic active agents from chewing gum
US20040185144A1 (en) * 2000-06-09 2004-09-23 Witkewitz David L. Method for making coated chewing gum products with a coating including an aldehyde flavor and a dipeptide sweetener
US7115288B2 (en) 2000-06-09 2006-10-03 Wm. Wrigley Jr. Company Method for making coated chewing gum products with a coating including an aldehyde flavor and a dipeptide sweetener
US6572900B1 (en) 2000-06-09 2003-06-03 Wm. Wrigley, Jr. Company Method for making coated chewing gum products including a high-intensity sweetener
US6444241B1 (en) 2000-08-30 2002-09-03 Wm. Wrigley Jr. Company Caffeine coated chewing gum product and process of making
US6663849B1 (en) 2000-09-01 2003-12-16 Wm. Wrigley Jr. Company Antacid chewing gum products coated with high viscosity materials
US6569472B1 (en) 2000-09-01 2003-05-27 Wm. Wrigley Jr. Company Coated chewing gum products containing antacid and method of making
US6579545B2 (en) 2000-12-22 2003-06-17 Wm. Wrigley Jr. Company Coated chewing gum products containing an antigas agent
US20190350946A1 (en) * 2017-08-04 2019-11-21 Poli Md S.R.L. Medical Device for the Treatment of HPV Cutaneous Infections
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