| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | December 30, 2003 |
| PATENT TITLE |
Dextromethorphan tannate |
| PATENT ABSTRACT |
The invention pertains to a composition comprising dextromethorphan tannate and to a method for preparing dextromethorphan tannate by reacting dextromethorphan at a temperature of about 80 to about 180.degree. C. with tannic acid either neat or as an aqueous slurry containing about 5 to about 30 wt. % water. The dextromethorphan tannate has extended release properties and is useful in pharmaceutical compositions as an antitussive for human beings. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | October 28, 2002 |
| PATENT REFERENCES CITED |
Sawai et al., JP -54034814 B4 (English Translation).* Sawai et al., HCAPLUS Copyright 2002 ACS, Accession #: 1980:135443; Abstract of JP 54034814 B4. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A composition comprising dextromethorphan tannate having a softening point from about 140-143.degree. C. to about 97-104.degree. C. when the dextromethorphan tannate has a corresponding moisture content ranging from about 2.8% to about 5.0%. 2. A therapeutic antitussive composition comprising a pharmaceutically effective amount of the composition of claim 1. 3. A therapeutic antitussive composition as claimed in claim 2 in tablet form. 4. A therapeutic antitussive composition as claimed in claim 2 in suspension form. 5. A therapeutic antitussive composition as claimed in claim 2 further comprising one or more expectorant and/or antihistamine compositions. 6. The composition of claim 5 wherein the expectorant and/or antihistamine compositions are selected from the group consisting of guaifenesin, chlorpheniramine, brompheniramine, pyrilamine, phenylephrine, ephedrine, pseudoephedrine, carbeta-pentane and carbinoxamine. 7. A method for suppressing coughing in a human being which comprises orally administering to such human being in need of cough suppression a therapeutic amount of the composition of claim 1. 8. A method as claimed in claim 7 wherein said composition is in tablet form. 9. A method as claimed in claim 7 wherein said composition is in suspension form. 10. A composition comprising dextromethorphan tannate having a tap density of about 0.7 to about 0.85 g/cc. 11. A therapeutic antitussive composition comprising a pharmaceutically effective amount of the composition of claim 10. 12. A therapeutic antitussive composition as claimed in claim 11 in tablet form. 13. A therapeutic antitussive composition as claimed in claim 11 in suspension form. 14. A therapeutic antitussive composition as claimed in claim 11 further comprising one or more expectorant and/or antihistamine compositions. 15. The composition of claim 14 wherein the expectorant and/or antihistamine compositions are selected from the group consisting of guaifenesin, chlorpheniramine, brompheniramine, pyrilamine, phenylephrine, ephedrine, pseudoephedrine, carbeta-pentane and carbinoxamine. 16. A method for suppressing coughing in a human being which comprises orally administering to such human being in need of cough suppression a therapeutic amount of the composition of claim 10. 17. A method as claimed in claim 16 wherein said composition is in tablet form. 18. A method as claimed in claim 16 wherein said composition is in suspension form. 19. A composition comprising dextromethorphan tannate containing substantially no unreacted dextromethorphan. 20. The composition of claim 19 wherein the amount of any unreacted dextromethorphan present in the composition is less than about 2 wt. %, based on the weight of the dextromethorphan tannate. 21. The composition of claim 20 wherein the amount of any unreacted dextromethorphan present in the composition is less than about 1 wt %, based on the weight of the dextromethorphan tannate. 22. The composition of claim 21 wherein the amount of any unreacted dextromethorphan present in the composition is less than about 0.5 wt. %, based on the weight of the dextromethorphan tannate. 23. A therapeutic antitussive composition comprising a pharmaceutically effective amount of the composition of claim 20. 24. A therapeutic antitussive composition as claimed in claim 23 in tablet form. 25. A therapeutic composition as claimed in claim 23 in suspension form. 26. A therapeutic antitussive composition as claimed in claim 23 further comprising one or more expectorant and/or antihistamine compositions. 27. The composition of claim 26 wherein the expectorant and/or antihistamine compositions are selected from the group consisting of guaifenesin, chlorpheniramine, brompheniramine, pyrilamine, phenylephrine, ephedrine, pseudoephedrine, carbeta-pentane and carbinoxamine. 28. A method for suppressing coughing in a human being which comprises orally administering to such human being in need of cough suppression a therapeutic amount of the composition of claim 20. 29. A method as claimed in claim 28 wherein said composition is in tablet form. 30. A method as claimed in claim 28 wherein said composition is in suspension form. 31. A composition of matter comprising dextromethorphan tannate having the following FTIR spectral analysis: Spectral Line, 1/cm Observation about 2950 Very slight depression about 2900 Flat about 1725 Moderate depression about 1625 Moderate depression about 1350 Moderate depression about 1200 Long depression about 1050 Moderate depression about 800 Small depression about 625 Long, narrow depression about 600 Long, narrow depression 32. A therapeutic antitussive composition comprising a pharmaceutically effective amount of the composition of claim 31. 33. A therapeutic antitussive composition as claimed in claim 32 in tablet form. 34. A therapeutic composition as claimed in claim 32 in suspension form. 35. A therapeutic antitussive composition as claimed in claim 32 further comprising one or more expectorant and/or antihistamine compositions. 36. The composition of claim 35 wherein the expectorant and/or antihistamine compositions are selected from the group consisting of guaifenesin, chlorpheniramine, brompheniramine, pyrilamine, phenylephrine, ephedrine, pseudoephedrine, carbeta-pentane and carbinoxamine. 37. A method for suppressing coughing in a human being which comprises orally administering to such human being in need of cough suppression a therapeutic amount of the composition of claim 30. 38. A method as claimed in claim 37 wherein said composition is in tablet form. 39. A method as claimed in claim 38 wherein said composition is in suspension form. 40. A method for preparing dextromethorphan tannate which comprises mixing dextromethorphan free base with tannic acid in the presence of 0 to about 30 wt. % water at a temperature of about 80 to about 180.degree. C. and thereafter recovering the resultant dextromethorphan tannate. 41. The method of claim 40 wherein the dextromethorphan is heated to a temperature of 110 to 150.degree. C. and water is present in the amount of 5 to 15 wt. %. 42. The method of claim 40 wherein the resultant dextromethorphan tannate is dried to a moisture content of about 5 wt. % or less. 43. The method of claim 40 wherein the dextromethorphan free base is employed in an amount of about 4 to about 8 moles of dextromethorphan per mole of tannic acid. 44. The method of claim 43 wherein the dextromethorphan is employed in an amount of 5 to 6 moles of dextromethorphan per mole of tannic acid. 45. The method of claim 40 wherein the resultant dextromethorphan tannate is milled to provide a free-flowing powder. 46. The method of claim 45 wherein the powder has a particle size in the range of about 50 to about 200 mesh. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The invention pertains to dextromethorphan tannate, its method of preparation and to pharmaceutical compositions containing dextromethorphan tannate. BACKGROUND OF THE INVENTION Dextromethorphan (hereinafter also referred to as dextromethorphan free base) is a well-known commercially available compound. It is the methyl ether of the dextrorotary isomer of levorphanol, anarcotic analgesic. Its chemical name is 3-methoxy-17-methyl-9.alpha., 13.alpha., 14.alpha.-morphinan and its CAS number is 125-71-3. It is a solid having a melting point of 109.5 to 112.5.degree. C. and its molecular formula is C.sub.18 H.sub.25 NO. It is insoluble in water, and therefore is utilized typically in the form of its hydrobromide monohydrate salt that is soluble in water. Dextromethorphan finds its principal use as an antitussive, i.e., a cough suppressant that acts centrally to elevate the threshold for coughing, but it does not have addictive, analgesic or sedative actions and does not produce respiratory depression with usual doses. It is typically administered to human beings in need of such medication in the form of tablets and/or suspensions. It frequently is administered as an antitussive/expectorant composition consisting of dextromethorphan hydrobromide monohydrate and guaifenesin. In contradistinction to the antihistamines, which are unstable in the form of their free bases, dextromethorphan is relatively stable. Therefore, little, if any attention, has been paid in recent years to improving dextromethorphan compositions. On the other hand, there is a considerable amount of prior art which has emerged in recent years directed to salts of antihistamines, principally tannate salts. For example, see U.S. Pat. Nos. 5,599,846; 5,663,415; 6,037,358; 6,287,597; and 6,306,904. U.S. Pat. No. 3,282,789 is directed to stable liquid colloidal tannate compositions. Examples 1-6 of this patent disclose formulations containing dextromethorphan tannate. However, no mention is made in the '789 patent as to the physical properties of the dextromethorphan tannate employed in the formulations nor is there any disclosure as to the method by which the dextromethorphan tannate was prepared. The patentees allude to several related patents involving the preparation of tannates of other materials by reacting a material with tannic acid in the presence of isopropyl alcohol employed as a solvent in the reaction mixture (such preparatory method is hereinafter referred to as the "IPA route"). Furthermore, the state of the art at the time of this patent was that tannates were always prepared by the IPA route. Such state of the art is also disclosed in one or more of the five U.S. patents identified above. Therefore, it is reasonable to assume that the dextromethorphan tannate employed in the examples of the '789 patent was prepared using the IPA route. Tannic acid is commercially available and is used in many industrial applications. It is frequently referred to as gallotannic acid, gallotannin; glycerite or tannin. It is a pale tan powder having a decomposition point of 210-215.degree. C., and is highly soluble in water and alcohols. Its molecular formula is C.sub.76 H.sub.52 O.sub.46 ; its CAS number is 1401-55-4. Tannic acid is typically produced from Turkish or Chinese nutgall and has a complex non-uniform chemistry and typically contains about 5-10 wt. % water. Dextromethorphan is quite stable and therefore would not require the addition of a material such as tannic acid to render it stable. Due to its water insolubility, dextromethorphan must, however, be utilized in the form of a salt, typically the hydrobromide monohydrate salt (hereinafter referred to as "dextromethorphan hydrobromide" or "dextromethorphan-HBr"). However, dextromethorphan hydro-bromide does have a drawback: it is readily absorbed in the patient's body, but its action is relatively short-lived. Accordingly, while it provides relatively quick cough sup-pression relief to the patient, the patient is required to take relatively high doses several times a day until the condition which necessitated the administration of the dextro-methorphan hydrobronide has been alleviated. It would be very desirable if a form of dextromethorphan was available which would have extended-release properties, i.e., the dextromethorphan would be slowly released into the patient's bloodstream over a prolonged period of time. Thus far, the only slow-release forms of dextromethorphan, which are available, are those such as polymer-coated tablets. Such prior art formulations provide mixed results in that the dextromethorphan is not available for adsorption into the patient's bloodstream until the polymeric coating has been dissolved, but thereafter the dextromethorphan is quickly absorbed and metabolized. The result is that frequently, the dextromethorphan hydro-bromide must again be administered to the patient within the period of only a few hours. DETAILED DESCRIPTION OF THE INVENTION It has now been found that it is possible to provide an extended-release form of dextromethorphan by reacting it with tannic acid so as to form dextromethorphan tannate, which differs dramatically from commercially available dextromethorphan tannate, or dextromethorphan tannate synthesized using the IPA route. The dextromethorphan tannate of the invention may be readily prepared by the following method: Dextromethorphan free base is obtained from a commercial source or a commercially available dextromethorphan acid salt such as dextromethorphan hydrobromide is treated with an aqueous base, e.g., 10% sodium hydroxide, to release the free base which is then washed to remove any sodium salts contained therein. Tannic acid is heated to a temperature in the range of about 80 to about 180.degree. C., preferably 110 to 150.degree. C., and the dextromethorphan free base is slowly added, while mixing, to the heated tannic acid slurry over a period of a few minutes to about one hour. Since the reaction mixture becomes very viscous and difficult to stir as the reaction proceeds, it is desirable to add about 5 to about 30%, preferably 5 to 15 wt. %, additional water before adding the dextromethorphan free base. The reaction mixture is continued to be stirred while maintaining such temperature range for a period of about 10 minutes to about 2 hours. Thereafter, the reaction mixture is cooled to room temperature. The resultant solid reaction mass comprising the dextromethorphan tannate is preferably thereafter milled to form a free-flowing powder preferably to a particle size of about 50 to about 200 mesh Since the dextromethorphan tannate product as prepared is moist, it may be dried to a moisture content of 5 wt. % or less by conventional methods, e.g., heat lamp, in a steam of air or nitrogen, vacuum drying, etc. at a temperature of about 20 to about 80.degree. C. for about 30 minutes to about 24 hours. However, the moisture content is relatively irrelevant in respect to its usage as a cough suppressant since the dextromethorphan tannate of the invention is intended to be ingested. The molar ratio of the dextromethorphan free base to the tannic acid is generally in the range of about 4 to about 8, preferably 5-6, moles of dextromethorphan per mole of tannic acid. The dextromethorphan tannate of the invention has the following physical properties: It has a softening point in the range of about 140.degree. C. when the product has a moisture content of about 3% and a softening point of about 100.degree. C. when the product has a moisture content of about 5% (the softening point is inversely related to the moisture content of the product). By contrast, commercially available dextromethorphan tannate has a softening point of about 174.degree. C. with a moisture content of about 5%, while dextromethorphan tannate synthesized via the IPA route has a softening point of about 172.degree. C. with a moisture content of about 5%. The dextromethorphan tannate of the invention is a tan-colored powder that is slightly soluble in water. The dextromethorphan free base is a white powder that is insoluble in water, while tannic acid is a tan powder that is soluble in water. The dextromethorphan tannate of the invention in the form of particles having a particle size of about 100 mesh has a tap density in the range of about 0.7 to about 0.85 g/cc, while both commercial available dextromethorphan tannate and dextromethorphan tannate synthesized via the IPA route in the form of particles having the same mesh size have a tap density of about 0.4 g/cc, or lower. A further and very important distinction between the dextromethorphan tannate composition of the invention relates to its purity level. Commercially available dextro methorphan tannate as well as dextromethorphan tannate synthesized using the IPA route contain relatively high levels of unreacted dextromethorphan free base, i.e., in the order of 2.5-6 wt. % (based on the weight of the dextromethorphan tannate) of unreacted dextromethorphan free base. In contra-distinction thereto, the dextro methorphan tannate of the invention contains substantially no unreacted dextromethorphan free base, i.e., the amount of such unreacted dextromethorphan free base in the dextromethorphan tannate composition of the invention will be less than 2 wt. %, typically less than 1 wt. % and often less than 0.5 wt. %. Further distinctions between the dextromethorphan tannate of the invention and dextromethorphan tannate synthesized via the IPA route may be found by comparing the spectra obtained by FTIR analysis as shown in Example 8 below. The dextromethorphan tannate of the invention may be prepared for oral administration in the form of pharmaceutically acceptable compositions such as powders, capsules, elixirs, syrups, etc. Preferably, the compositions are prepared in the form of tablets containing about 10 to about 100 mg of dextromethorphan tannate per tablet or as a suspension, i.e., a liquid, wherein each 5 ml (teaspoon) of liquid would contain about 5 to about 60 mg of the dextromethorphan tannate. Tablets containing the unique dextromethorphan tannate of the invention may be prepared in a conventional manner by the addition of suitable pharmaceutical carriers, including fillers, diluents, lubricants and the like as well as conventional and well known binding and disintegrating agents. A typical tablet composition of the present invention will contain, in addition to the dextromethorphan tannate, microcrystaltine cellulose, corn starch, magnesium stearate, croscarmellose sodium and coloring matter. The suspension formulations of the dextromethorphan tannate of the present invention will typically additionally contain citric acid, caramel, glycerin, sorbitol solution, propylene glycol, saccharin sodium, sodium benzoate, flavoring agent and purified water. If desired, the dextromethorphan tannate of the invention may be formulated with other pharmaceutically active ingredients such as antihistamines and antitussives, e.g., chlorpheniramine, dexchlorpheniramine, brompheniine, dexbrompheniramine, pyrilamine, phenylephrine, ephedrine, pseudoephedrine, carbetapentane, carbinoxamie, guaifenesin, and the like. Typically, these other active ingredients will be employed in the form of their free bases or as their salts, e.g., citrates, maleates, hydrobromides, hydrochlorides, tannates, etc. Of course, the dosage of the dextromethorphan tannate of the present invention, alone or in combination with other pharmaceutically active ingredients to be administered, will be dependent on the age, health and weight of the recipient, types of concurrent treatment, if any, frequency of treatment and effect desired |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
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