llllllllllllll ll Ill lllllllllllllllll 11111
`
`USOO6417206B1
`
`(10) Patent No.:
`(12) United States Patent
`Leflein et al.
`(45) Date of Patent:
`
`
`US 6,417,206 Bl
`Jul. 9, 2002
`
`(54) ANTITUSSIVE/ANTIHIST AMINIC/
`DECONGESTANT COMPOSITIONS
`
`6,306,904 Bl
`
`10/2001 Gordziel
`
`..................... 514/530
`
`FOREIGN PATENT DOCUMENTS
`
`(75)
`
`Inventors: Ronald Leflem, East Hanover;
`Alexander D. D’Addio, Piscataway,
`both of NJ (US)
`
`JP
`
`64007786
`
`*
`
`8/1993
`
`OTHER PUBLICATIONS
`
`(73) Assignee: MedPointe Healthcare Inc., New York,
`NY (US)
`
`Luchem, DrugLaunch (Accession No: 94: 41007) Jul. 29,
`1991 .*
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(1)) by 0 days.
`
`Weiler et 31-, Ann. Allergy, 64(1), 63—67 1990 (abstract).*
`
`* Cited by examiner
`
`(21) App]. No.: 09/771,130
`_
`(22) Filed:
`
`Jan. 26, 2001
`
`Pn'mary Examiner—Phyllis Gr Spivack
`(74) Attorney, Agent, or Firm—4311101 M. Olstein; Raymond
`E. Slaujrer
`
`(51)
`
`Int. Cl.7
`
`A61K 31/216; AélK 31/4402;
`A61K 31/137
`
`(57)
`
`ABSTRACT
`
`........................ 514/352; 514/530; 514/653
`(52) us. (:1.
`(58) Field of Search
`514/352, 530,
`514/653
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`Tannate compositions are disclosed consisting emntially 0f
`carbetapcntanc tannate, pyrilamine innate and phenylcph-
`rine tannate are elfective when administered orally for the
`symptomatic relief of cough associated with respiratory tract
`conditions such as the common cold, bronchial asthma,
`acute and chronic bronchitis.
`
`6,287,597 B1
`
`9/2001 Gordziel
`
`..................... 424/464
`
`14 Claims, N0 Drawings
`
`
`
`000001
`
`Exhibit 105 6
`
`Exhibit 1056
`IPR2017-00807
`ARGENTUM
`
`IPR2017-00807
`
`ARGENTUM
`
`000001
`
`

`

`US 6,417,206 B1
`
`2
`
`1
`
`ANTITUSSIVE/ANTIHIST AMINIC/
`DECONGESTANT COMPOSITIONS
`
`FIELD OF INVENTION
`
`5
`
`10
`
`15
`
`20
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`The invention relates to novel antitussive/antihistiminic/
`decongestant tannate compositions. The compositions con-
`tain as essential ingredients carbetapentane tannate, pyril-
`amine tannate and phenylephrine tannate.
`
`BACKGROUND OF INVENTION
`
`A considerable number of tannic acids occur in nature.
`Chemically, these acids are described as polymers of dilfer—
`ent hydroxybenzoic acids. Generally, when the term tannic
`acid is employed, as in the present case, the acid referred to
`is gallotannic acid,
`the internal ester of gallic acid also
`frequently referred to as tannin.
`
`Tannic Acid consists of an amorphous powder glistening
`scales or spongy masses Varying in color from yellowish-
`white to light brown. Tannic acid is very soluble in water,
`glycerine or alcohol.
`Tannic acids are usually obtained from glycosides which
`consist of several molecules of a tannic acid in combination
`with glucose.
`tannic acid, also known as
`Commercially available,
`Tannin, has a complex non-uniform chemistry, usually con~
`tains from about 5% to about 10% by weight water, has a
`molecular weight of about 1700, and is typically produced
`from Turkish or Chinese nutgall.
`Carbetapentane, known chemically as 2—[2—
`(diethylamino)ethoxy]ethyl
`1-phenylcyclopentanecarboxylate is an antitussive com-
`pound that is described in U.S. Pat. No. 2,842,585 and is
`structurally related to caramiphen. Carbetapentane citrate
`has a melting point of 93° C. and occurs as a white powder
`freely soluble in water and slightly soluble in alcohol.
`Carbetapentane has an atropine-like action that depresses
`the cough reflex by selective central nervous system depres—
`sion.
`
`Pyrilamine is one of the oldest and most enduring anti-
`histaminic drugs, known chemically as N-[(4—
`methoxyphenyl)rnethy]]-N’,N'-dimethyl—N-2-pyridinyl-1,2-
`ethanediamine, its preparation is disclosed in U.S. Pat. No.
`2,502,151 and is an oily liquid. Pyrilamine hydrochloride
`salt is very soluble in water and has a melting point of
`143—1435" C. whereas the maleate salt is slightly soluble in
`water, benzene and ether and has a melting point of
`100—1 01° C.
`
`Phenylephrine, known chemically as (—)—m-hydroxy-a-
`[(methylamino)—methyl] benzyl alcohol, is a synthetic, opti-
`cally active sympathomimetic amine which has one
`hydroxyl group on the benzene ring. The hydroxyl group is
`placed in the position meta to the aliphatic side chain. The
`meta position affords optimal activity and phenylephrine
`(neo-synephrine) replaced an older preparation, synephrine,
`in which the hydroxyl was in the para position.
`Phenylephrine hydrochloride is available in the form of
`the levorotatory isomer, a white, odorless, non-hygroscopic,
`crystalline compound possessing a bitter taste. Phenyleph—
`rine hydrochloride has a melting point of 140—145“ C. and
`is freely soluble in water and alcohol.
`Antitussive, antihistamine and decongestant compounds
`in the form of their free bases as well as their salts, e.g.
`hydrochloride, citrate, maleate,
`tannate, etc., are well
`known. Antitussives, antihistamines and decongestants in
`the form of their tannate salts are very desirable because
`
`such salts are generally stable and may be combined in such
`form without any untoward side elIects.
`Antitussives, antihistamines and decongestants in the
`form of their tannate salts are typically prepared by reacting
`the free base, e.g. carbetapentane, pyrilamine,
`phenylephrine, etc. with tannic acid in the presence of a
`volatile solvent, usually isopropanol. Typically, in the con-
`ventional isopropanol route, the antitussive, antihistaminic
`or decongestant free base and the tannic acid will be present
`in the isopropanol at a concentration of about 20% based on
`the weight of the reaction mixture. The reaction mixture is
`stirred for about one hour while maintaining the mixture at
`60—70° C. The reaction mixture is cooled to room tempera-
`ture and then filtered, washed with isopropanol and then
`vacuum dried. Alternative routes to the tannate salts are
`described in U.S. Pat. No. 5,599,846 and U.S. Pat. No.
`5,663,415.
`
`THE INVENTION
`
`the novel combination of
`It has now been found that
`carbetapentane tannate, pyrilamine tannate and phenyleph-
`tine tannate produces a composition having antitussive,
`antihistaminic and sympathomimetic decongestant proper-
`ties superior to the use of any one of the tannate compounds
`alone.
`
`The compositions of the present invention may be pre—
`pared for oral administration in the form of powders,
`capsules, elixirs, syrups and the preferred forms of tablets or
`suspensions formulated so that ideally each tablet contains
`approximately 50 to 75 mg of carbetapentane tannate, pref—
`erably about 60 mg of carbetapentane tannate, approxi-
`mately 30 to 50 mg pyrilamine tannate, preferably about 40
`mg of pyrilamine tannate, and approximately 5 to 15 mg
`phenylephrine tannate, preferably about 10 mg phenyleph-
`rine tannate or that ideally each 5 mL (approximately 1
`teaspoon) of suspension would contain approximately 20 to
`30 mg carbetapcntane tannate, preferably 30 mg of carbe-
`tapentane tannate, 25 to 30 mg pyrilamine tannate, prefer-
`ably 30 mg of pyrilarnine tannate, and 3 to 8 mg of
`phenylephrine tannate, preferably 5 mg of phenylephrine
`tannate,
`
`Tablets containing the unique tannate combination of the
`present invention are prepared in a conventional manner by
`the addition of suitable pharmaceutical carriers including
`fillers, diluents, colorants, lubricants and the like as well as
`conventional and well known binding and disintegrating
`agents. A typical tablet composition of the present invention
`containing starch, dibasic calcium phosphate, colorants,
`magnesium stearate, methylcellulose, polygalacturoic acid,
`povidone and talc as described in Example 1 which follows
`is prepared by well known conventional tabletting tech-
`niques such as those disclosed in U.S. Pat. Nos. 3,018,221;
`2,798,024 and 2,757,124.
`
`EXAMPLE 1
`
`Carbetapentane Tannate, Pyrilamine Tannate and
`Phenylephrine Tannate Tablets
`
`
`
` Ingredient Milligrams per Tablet
`
`Carbetapentane Tannate
`60.0
`Pyrilamine Tannate
`40.0
`Phenylephrine Tannate
`10.01
`
`000002
`
`000002
`
`

`

`3
`
`4
`
`US 6,417,206 B1
`
`~continued
`
` Ingredient Milligrams per Tablet
`
`Starch. NF
`65.0
`Mclhylcellulose, USP
`150
`Polygalacturoic Acid
`32.0
`Dihasic Calcium Phosphate, USP, Dihydrate
`65.0
`Povidonc, USP
`25.0
`Talc, USP
`5.4
`FD&C Red #40 Aluminum Lakee40%
`3.93
`Magnesium Stearate, N'F
`4.0
`
`Alcohol Specially Denatured 23A 190 Proof 1402
`115% excess added during manufacturing
`2Not present in the finished tablet product
`
`5
`
`10
`
`15
`
`Suspensions of the compositions of the present invention
`are prepared in a conventional manner such that each 5 mL
`(one teaspoon) contains:
`20
`Carbetapentane Tannate
`30 mg
`Pyrilamine Tannate
`30 mg
`
`Phenylephrine Tannate 5 mg
`
`The suspension formulations additionally contain benzoic
`acid, colorants, natural and artificial
`flavors, glycerin,
`kaolin, magnesium aluminum silicate, methylparaben,
`pectin, purified water, saccharin, sodium hydroxide and
`sucrose or sorbitol.
`is illustrative of a typical
`Example 2, which follows,
`suspension formulation of the present invention prepared by
`conventional well known compounding techniques.
`EXAMPLE 2
`
`Carbetapentane Tannate, Pyrilamine Tannate and
`Phenylephrine Tannate Suspension
`
`
`
` Ingredient Milligrams per 5 mL
`
`Carbetapentane Tannate
`30.0
`Pyrilaminc Tannate
`30.01
`Phenylephrine Tannatc
`5.02
`Pectin, USP (Medium Viscosity)
`50.0
`Kaolin, USP (Colloidal Powder)
`1000
`Magnesium Aluminum Silicate, NF
`35.0
`Benzoic Acid, USP
`10.0
`Methylparaben, NF
`2.5
`Sucrose, NF
`1000
`Saccharin Sodium, USP
`0.75
`Glycerin, USP
`225
`Flavor Black Currant Imitation
`0.9]
`Flavor Strawberry with Other Natural Flavors
`2.23
`Purple Shade “"R Dye
`0.45
`FD&C Red #3 Dye
`0.8
`FDSZC Yellow #5
`0.3
`Sodium Hydroxide Solution-50%
`0.7933
`
`Purified Water, USP (Deionized) adjust to 5 mL
`
`‘S% excess added during manufacturing
`215% excess added during manufacmring
`3The quantity of Sodium Hydroxide Solution may be varied depending on
`the pH of the Kaolin used in the batch. Tannic acid may also be used in
`lieu of sodium hydroxide solution for pH adjustment. Sodium Citrate,
`USP, Dihydrate and Citric Acid, USP, Anhydrous may also be included in
`the formula for pH adjustment.
`
`For the purpose of this disclosure, a warm-blooded animal
`is a member of the animal kingdom possessed of a homeo-
`static mechanism and includes mammals and birds.
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`The dosage administered will be dependent on the age,
`health and weight of the recipient, kinds of concurrent
`treatment, if any, frequency of treatment and etiect desired.
`It should be understood that
`the above examples are
`illustrative of the best mode only of the invention herein
`disclosed. Given the present disclosure, it is anticipated that
`numerous Variations will occur to those skilled in the art. A
`latitude of modification, substitution and change is intended
`and in some instances, some features of the invention will be
`employed without a corresponding use of other features.
`Accordingly, it is intended that the spirit and scope of the
`invention disclosed herein should be limited only by the
`following claims.
`What is claimed:
`
`1. Atherapeutic composition for the symptomatic relief of
`cough associated with adverse respiratory tract conditions in
`warm—blooded animals in need of such treatment said com-
`position comprising pharmaceutically effective amounts of
`active ingredients, wherein said active ingredients consist of
`carbetapentane tannate, pyrilamine tannate and phenyleph-
`rine tannate.
`
`2. The therapeutic composition of claim 1 in tablet form.
`3. The therapeutic composition of claim 2 wherein each
`tablet contains 50 to 75 mg of carbetapentane tannate, 30 to
`50 mg of pyrilamine tannate and 5 to 15 mg of phenyleph—
`rine tannate.
`
`4. The therapeutic composition of claim 2 wherein said
`tablet form contains about 60 mg of cabetapentane tannate,
`about 40 mg of pyrilamine tannate, and about 10 mg of
`phenylephrine tannate.
`5. The therapeutic composition of claim 1 in suspension
`form.
`6. The therapeutic composition of claim 5 wherein 5 ml.
`of the suspension contain 20 to 30 mg of carbetapentane
`tannate, 25 to 30 mg of pyrilamine tannate and 3 to 8 mg of
`phenylephrine tannate.
`7. The therapeutic composition of claim 5 wherein said
`suspension form contains about 30 mg of cabetapentane
`tannate, about 30 mg of pyrilamine tannate, and about 5 mg
`of phenylephrine tannate, per 5 m1.
`8. A method for symptomatically treating and relieving
`the distress of cough associated with adverse respiratory
`tract conditions in warm-blooded animals comprising orally
`administering to warm-blooded animals in need of such
`treatment of the composition of claim 1.
`9. The method of claim 8 wherein said composition is in
`tablet form.
`10. The method of claim 9 wherein each tablet contains 50
`to 75 mg of carbetapentane tannate, 30 to 50 mg of pyril-
`amine tannate and 5 to 15 mg of phenylephrine tannate.
`11. The method of claim 9 wherein said tablet form
`contains about 60 mg of cabetapentane tannate, about 40 mg
`of pyrilamine tannate, and about 10 mg of phenylephrine
`tannate.
`
`12. The method of claim 8 wherein said composition is a
`suspension.
`13. The method of claim 12 wherein 5 ml. of the suspen—
`sion contain 20 to 30 mg of carbetapentane tannate, 25 to 30
`mg of pyrilamine tannate and 3 to 8 mg of phenylephrine
`tannate.
`
`14. The method of claim 12 wherein said suspension
`contains about 30 mg of cabetapentane tannate, about 30 mg
`of pyrilamine tannate, and about 5 mg of phenylephrine
`tannate, per 5 ml.
`
`000003
`
`000003
`
`