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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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anhydride
acid
milligrams
acetylsalicylic
asa
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US729258A
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Edward H Lincoln
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Pharmacia and Upjohn Co
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Upjohn Co
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Priority to NL121097D priority patent/NL121097C/xx
Priority to BE585778D priority patent/BE585778A/xx
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Priority to US729258A priority patent/US2990328A/en
Priority to GB9597/59A priority patent/GB885081A/en
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    • 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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Description

United States Patent z 990 32s STABLE 'IHERAPEUTIC coMrosrrioNs CON- a u gr vo ACETYLSALICYLIC ACID-ANHY- Edward H. Lincoln, Kalamazoo Mich. assignor to The fipjglhn Company, Kalamazoo: Mich; a corporation of c gan No Drawing. Filed Apr. 18, 1958, Ser. No. 729,258 8 Claims. (Cl. 167-55) This invention relates to therapeutic compositions and more particularly to therapeutic compositions possessing analgesic, antipyretic and antirheumatic properties.
A wide variety of substances and compositions possessing analgesic, antipyretic and antirheumatic properties is known in the This variety, which includes such chemically and physiologically difierent substances as bromides, colchicine, hormones, iodides, addictive narcotics and salicylates, has resulted from unceasing endeavor to obtain relief from the pain and sufiering accompanying the multitude of afilictions which beset human beings. Throughout the years, which can now be counted in decades, acetylsalicylic acid has gained and retained a place in the foreground through its beneficial analgesic, antipyretic and antirheumatic actions. It is believed that the said beneficial actions depend, in a large measure-on the systemic efiects of the blood levels of salicylate, including the esten'fied compound acetylsalicylic acid.
Accompanying the beneficial properties of acetylsalicylic acid are certain chemical and physiological properties which result in distressing side-effects. Acetylsalicylic acid is known to decompose to the irritating compounds,
acetic and salicylic acids. Also, acetylsalicylic acid is known to be an irritant to the gastric mucosa.
Prior to the present invention, it was not known how to provide a stable, solid therapeutic composition, in dosage unit form, which unexpectedly yields faster, higher blood levels of salicylate including the esterified compound, acetylsalicylic acid.
It is an object, therefore, of the present invention to provide therapeutic compositions which yield faster,
higher blood levels of salicylate including acetylsalicylic acid. 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. Other objects will be apparent to those skilled in the art to which this invention pertains.
The foregoing and related objects have been accomplished by the provision of a stable, solid oral therapeutic preparation in dosage unit form comprising [acetylsalicylic acid]-anhydn'de, and a pharmaceutically acceptable non-alkaline diluent containing a pharmaceutically acceptable acidic substance, which diluent does' not lower substantially the melting point of said anhydride.
I! II O-G-CH: HaC=CO a l Methods-of preparation are described in Handbuch der Organischen Chemie, Beilstein, first edition, volume X, page 85, and in Organic Chemistry, Richter, volume 2, page 330, 1919. The anhydride has a melting point of C. Thus, it is apparent that the chemical compound [acetylsalicylic acid]anhydride has been available for many years. However, until' the present invention, the superiority of solid [acetylsalicylic acid] -anhydride preparations in dosage unit forms was unknown and the successful preparation of said compositions was unrealized.
'Ilheterm" dosage unit form as used in this specification 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. Examples of 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.
As usedin the specification and claims the term 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. When some of the material in the particular diluent used, or in the environment in which it is stored (including soft glass), is slightly alkaline, the presence of an acidic substance in the diluent will bring the overall environment back to substantially neutral or acidic condition with the result that the stability of the [acetylsalicylic acidJ-anhydride is not afiected adversely. This alkaline deterioration is more pronounced at temperatures above 25 degrees centigrade.
drideby the diluent causes deterioration of-the active ingredient, in some cases actually resulting in liquefaction. The experimental data at temperatures above 25 degrees centigrade show the seriousness of this deterioration and indicate that physical and chemical deterioration will occur under some shipment and storage conditions which are often encountered in the trade.
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. As 'used in the Specification and claims the term 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.
As used in the specification and claims the term acidic.
substance is used in reference to pharmaceutically acceptable 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.
Micronized [acetylsalicylic acidl-anhydride (i.e., having a particle size 7 i found to produce advantageous results.
Complementary and coacting active ingredients can be added to the compositions of this invention. Illustrative of said 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.
The compositions of this invention possess analgesic,
antipyretic and antirheumatic properties and are useful in therelated afilictions and disorders susceptible to such properties.
Initial attempts to prepare the compositions of the instant invention were unsuccessful. It was unexpectedly discovered that certain conventional diluents exerted deleterious effects on the active ingredient, [acetylsalicylic acidl-anhydride. Said deleterious elfects were observed during the preparation of the usual dry admixtures fort.
less than about ten microns) has been subsequent manufacturing steps. It was observed that hydrolysis and deterioration of the [acetylsalicyclic acid]- ate.
[ASAl-Anhydrlde Magnesium anhydn'de to the point of liquefaction occurred in some admixtures. Therefore, accelerated stability studies were performed to ascertain the compatibili-ties and incompatibilities of the active ingredient. These studies showed, unexpectedly, that various conventional diluents used for bulking, binding, lubrication and like actions could not be used with [acetylsalicyclic acidl-anhydride. Tables I and II contain the data on the effect of the various diluents without an acidic substance.
TABLE L-[AOETYLSALICYLIC ACID1-ANEYDRIDE 1-5? STABILITY. F WQEBMIXT X [5 parts enhydride: 1 part dtluentl V 1 Week at 47 0.
or u a. 1 i v I {ASA} ASA Salicylic Anhydride Acid [Asfl-anhydride starch,115.1; 282.6 mg--- 23.1 mg Negative. [A1834 Etnhydride Starch, U.S.P.', 282.0 mg... 21.3 mg Do.
me [ASAl-Anhydride Talc, U.S.P. 285.9 mg... 16.2 mg Do. [ASAl-AnhydrideCalelum Stear- 117.3 mg--- 56.1 mg- 3.3 mg.
" Mixture liquid after one day. No assay. Condition very poor.
Stearate. [AS'Al-Anhydride Stearic Acid- [ASA}-Anhydride Sterotex No assay. Condition poor.
[ASA- ydride Methylcellu- 123.9 mg..- 8l.6,mg. 1.8 mg.
dose, U131; Control 297.0n1g 51mg.-. Negative.
1 Theory=300 milligrams. ASA=acetylsalicylic acid. sterotex hydrogenated vegetable 011.
TABLE II.- AG'E'IYLSALICYLIO AOID]-ANHYDRIDE STABILITY (POWDER MIXTURES) [5 parts anhydrldezl part diluent} 1 Week at 47 0.
Formula {ABA} Salicylic Anny! ASA, mg. Aeid,mg. dride, mg
[ASA dlgnhydride Cane Sugar, 287.1 s. 1 2.1. [afiltzl anhydride Gunr Gum 2 38.5 44.7 1.5. [AsAl Allhydllde Dlcalclum 292.8 6.0 1.2.
Phosphate. [Azsozofl-Anhydflde Solka-Floc BW 286.8 9.3 2.4. [ASAl Anhydride Calcium Oar- 244.2 18.0 2.4.
bonate, use [ASAl-Anhydride Oarboxymeth- 160.5 117.6 Negative.
ylcellulose. Y [AsAa-Anhpydrlde Lactose, U.S. P- 293. 7 5. 1 Do. [ASA =Anhydride Veegum H.V- 216. 3 65. 1 Do. Control'L 4.-..-. 293.1 4.8 0.9.
1 Theory=300 milligrams. ASA=acetylsal1c lie acid. Solka-F1oc=purlt 1ed wood cellulose.
Y awar n ss- 1 almisa Silicate- The deleterious efiects of certain of the diluents of Tables Ifa're'not thoroughly understood. However, it is various diluents h' ithoutan acidic substance.
Initial 2Weeks Formula Mois- [ASA]- 5911- [ASAl- Salicylic Acid,
ture, Anhy- ASA cylic Anhy- ASA, mg. Percent dride, Acid, dride, mg
mg. mgs. mg.
ASA -Anh dride Starch, Aca- 168.3 57.0 Neg. 47 0.). Asiii drid $92 11 s 8 298,2 Neg-n 0.3 9 9 517 55 -Anhy e rc orbitol,Talc. 296-4 Negm M i 1 pr eg gos g1 I e? 229 2 .2 9 92529 89 A A-Anhy i e tarc an- T. l ass- AA- yie ac arc Dicalcium Phosphate. 306-3 283.8 12.9 3.9 40 03.
1 Month Formula [ASAI- ASA, Salicyclic Acid, nhy flde, mg mgs.
I [ASA]-Anhydride, Starch, Acacia, Talc- 289.8 0.9 Neg. (25 0.). 197. 1 81.0 0.9 (47 0.). [ASA]-Anhydride, Starch, Sorbitol, Talc 274.8 9. 6 1.8 (40 0.).
291.0 Neg. Neg. 25 0.). [ASA]-Anhydrlde, Starch, Sorbitol, Talc. Tablets dried in 8 vacu m 299.4 Neg (2552 530.). [ASA]-Anhydride, Starch, Mannitol, Talc "2693 "ii? 0.6 40' 0.
296.1 Neg. ldggi)? 0.). [ASA]-Anhydride, Talc, Starch, Dicalcium Phosphate "2913 "263 4.6 40 0.
301.2 Neg. Neg. (25 0.). ASA=acetylsalicylic acid.
The data of Table III indicate that short-term room temperature storage would not be harmful to the active ingredient with certain diluents, but also indicate that temperatures often encountered in shipment and storage would be harmful to preparations made without the presence of an acidic substance to counteract the alkalinity from the soft glass container and from any alkaline substance in the diluent, e.g., talc.
As is clearly shown by the foregoing stability studies on specific compositions containing a non-alkaline diluent but no including an acidic substance, such a compoover those contain- The presence of an TABLE IV.[AOETYLSALIOYLIO AOID]-ANHYDRIDE STABILITY (COMPRESSED TABLETS) Initial 2 Weeks Formula Moisture [ASA]- Salicylic [ASAl- ASA .Salic lie percent Anhydride, ASA Acid, Anhydride, m A in mg. mgs. mg. [Aggl-Anhydride, Starch, Talc, Ascorbic L0 3123 [ASAl-Anhydride Starch Sorbitol Talc 29139 013 11.9 47 o.' Citric Acid. 297-6 295.8 Neg. 2.1 $1030. Do 1.0 299.1 Neg 0.6 2; [ASAI-Anhydride, Talc, Starch, Dicalcium 0 72 302 4 0 3 269.4 20.7' 21 47 01): Phosphate, Ascorbic Acid. 287. 1 7. 8 1.8 40" 0.).
1 Month 2 Months Formula {ASA} ASA Salicylic [ASAJ- ASA Salicylic Anhydride, mg. d, mgs. Anhydride, mg. A d, mgs.
mg. mg.
268.5 [ASA]-Anhydride, Starch, Talc, Ascorbic Acid (2 29314 3.9 Neg. (47 0 276.4 21.3 1.5 4' 0. [Agkfllijanhydrida Starch, Sorbitol, Talc, Citric 2? 1 335 8) V N2; 9 0 e 295.8 1.2 1 5 47 0 272.7 19.8 2.4 47 0. lAggi hydnde, Starch, Sorbitol, Talc, Cm'ic g g g E 8 2955 N 3 eg. eg. 25 306.0 eg. 0.9 25 0.). 270.0 29.1 5.7 (47C. [ASA1-Anhydride, Talc, Starch, Dicalcium 287 4 9 9 0 9 0 271 2 24 6 1 e .5 (40 0. 4 297.9 Neg Neg. 25 0. 295.5 5.7 Neg. 25 1).
ASA=acetylsalicy1ic acid.
ass age These data in Table IV show that the invention.is.S1 Q--.-, cessful in providing compositions in which the active; ingredient, [acetylsalicyclic acidJ-anhydrideresists de-- terioration under severe temperature conditions;
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.
TABLE V.MIXTURE STABILITY- hoaryLsAmoYLroa AOID1-ANHYDRIDE:
Ql We k. t en de Acidic Substance l fi l- ASA, l cy Anhydride, percent Acid,
percent percent 94,0 5.2 o4 Tartaric acid 101 .4. t 0.8. Neg. Malic acld 90.1 1.,0, Neg Lactic acid I 63.1 1 9.7 0.9 Glutamic acid H01. 94. 3 6. 4 0. Pyridoxlne 98. 8 1. 4 Ne Ascorbic acid 98. 5 I 1. 9 0. Nicotinic acid- 97. 6 3. 5 0. Citric acid.-- 97. 8 2. l 0. Control 72. 8 1 6.0 0.
1 Liquefied.
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.
The addition to the above formula, per tablet, of 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.
Similarly, 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-.
[acetylsalicylic acidJ anhydrideresIHting from the use of an acidic substance which does not afiect deleteriously the melting point of the [acetylsalicylic acid] -anhydride.
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
TABLE VI One Week at 56 Centigrade Grams of OitrieAcid $5M- ABA, Salicylic A ydride, percent Acid,
percent percent 0.7 0.1 1. 9 Neg. 2. 1 0. 1 1. 8 0. 1 1. 5 Neg. 0. 9 Neg. 1 6.0 0. 4
The data in Table VI show the superiorstability resulting from the use of citric acid in an amount as small as one part'to 300 parts of [acetylsalicylie acidI-anhydride.
Theifollowing examples are illustrative of the compositions ofthisinvention but are not to be construed as it n EXAMPLE 1 Compressed tablets 25,000 compressed'tablets each containing 300 milligrams of [acetylsalicylic acidyanhydride, and 10 milli-. grams. ofcitric acid-are prepared from the following-types Y and amounts ofingredients; r
hydride by the calculated amount of the anhydride.
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.
EXAMPLE 2 Hard-filled capsules Each capsule contains:
, Milligrams [Acetylsalicylic acid]-anhydride 300 Tartar-ic acid 20 Starch, dried 120 Talc EXAMPLE 3 Chewing gum Pieces of. uncoated chicle chewing gum weighing approximately one gram each are used as starters for the coating process. A coating of sucrose is first applied, using a syrup containing approximately eighty percent of sucrose by weight, in themsual coating pan. A finely powdered highly hydrogenated castor oil (Thixcin), is then dusted on the'sucrose-covered starters. The second coating step uses a dispersion of micronized [acetylsalicylic acidbanhydride and pyridoxine hydrochloride in absolute ethanol. This suspension adheres to the oil layer and permits rapid drying between successive coat- [Acetylsalicylic acidl-anhydride grams 7500 Granulation mixture:
Starch, bolted do 645 d-Sorbitol solution, 70 percent .do 645 Deionized water milliliters 5160 Citric acid grams 250 Lubricant mixture: v
. tarqhiho isd e "-9-"? 403. Talc, bolted do 806 ings with the active ingredient. Eight to ten successive coatings are applied to give a gum containing fifty milligrams of acetylsalicylic acid] -anhydride. Thereafter, 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.
EXAMPLE 4 Powder packet A powder packet isprepared from-the following types and amounts of ingredients.=
9 Each packet contains:
' Milligrams [Acetylsalicylic acid]-anhydride 1000 Starch, dried 150 Malic acid 40 Talc, dried 200 The ingredients are mixed and milled to a particle size of approximately forty mesh and filled into plastic-coated paper or aluminum foil packets. The ingredients in such packets are satisfactory for preparing a dispersion in water, milk, fruit juices and the like, for oral administration.
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.
ing from about 0.25 to about one milligram of reserpine per capsule.
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.
EXAMPLE 10 Compressed tablets Following the procedure of Example 1, a compressed tablet is prepared containing in each tablet:
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.
It is to be understood that the invention is not to be limited to the exact details of operation or compositions shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.
What is claimed is:
1. 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.
2. 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.
3. 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.
4. 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 noualkaline 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.
5. 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.
6. 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.
7. 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.
8. 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; V V ReferencesrCifedl in the file of this patent UNITED STATES PATENTS 922,766 Hfmann May 25, 1909' 2',888,382- Plyte et a1. May 26, 1959 12 OTHER REFERENCES" Hackhs Chenfical Dictionary, 3rd ed., Blakiston Co., p.'377, 1944. V, ,7 V I Howard: ModelIl-Drug Encyclopedi 6 h; d, Drug 5 Pam. Inc., New York City pp. s7 and379,"1955.
Physicians" Desk Reference,-11th ed., Medical Eco nomics Inc., Oradell, New Jersey, 591, 1957.
Drug Trade News, p. 56, Dec.16, 1957.

Claims (1)

1. 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 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.
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Cited By (31)

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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

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Cited By (39)

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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
US10993950B2 (en) * 2017-08-04 2021-05-04 Poli Md S.R.L. Medical device for the treatment of HPV cutaneous infections

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