JPH11502839A - Antitussive microcapsules - Google Patents

Abstract

  (57) [Summary] The present invention relates to a composition for use in the treatment of cough and / or sore throat, in the form of microcapsules.

Description

Description: TECHNICAL FIELD The present invention relates to a composition in the form of microcapsules for use in the treatment of cough and / or sore throat. BACKGROUND OF THE INVENTION The cough reflex is an important mechanism by which secretions from the lungs and airways are removed. Generally, such secretions are removed by a mucociliary escalator. However, if this mechanism is incomplete or overwhelmed, for example by excess secretions, then coughing is an essential means of secretion removal. The cough reflex is initiated by the stimulation of a mechanical receptor and is controlled by afferent pathways in the vagus (X), glossopharyngeal (IX) and nasopharyngeal nerves to the cough center of the brainstem. Cough can be caused, for example, by foreign substances, dust, mucous membranes, debris, gas and smoke in the lower respiratory tract. Stimulation of various sensory nerves in the nose, sinuses, pharynx, ears, stomach, pericardium or diaphragm can also cause coughing. However, in many of these conditions, a chronic or paroxysmal cough can be exhausting and debilitating, especially if it interferes with sleep. Oral cough preparations, such as tablets, lozenges, syrups, solutions, suspensions and the like, contain effective antitussives and have long been used for the relief of cough symptoms. The most common of such formulations include dextromethorphan (or its hydrobromide) or codeine (or its sulfate) as an effective antitussive. These treatments are described, inter alia, in Drug Evaluation, 6th edition, Chapter 21 (The American Medical Association. 1986). In general, cough syrups and sore throat medicaments are available as pourable liquids or thixotropic gels. Examples of prior art gel formulations for the treatment of cough include those described in US Pat. No. 4,427,681. This document is incorporated herein by reference. In this document, a suspending agent (Avice / R R-591 from FMC Corporation) which gives thixotropic properties to the formulation is used, which has a high viscosity and is specially designed for pouring. Requires an appropriate amount of shearing force by a suitable device or dispensing nozzle. Other formulations include the well-known liquid gelatin capsules; however, which tend to be swallowed, thereby providing no coating of the oral mucosa. Other liquid gelatin capsules intended for chewing have a thick gelatin shell, which dissolves slowly, or after release of the active or no longer the user wants the outer capsule in the mouth. If not, you need to exhale. GB 1,060,258 discloses tablets (pastilles) having a thick outer gelatin layer containing the active, which are licked or chewed until the active in the core is released. The remaining gelatin shell is then chewed in the mouth until dissolved. Such conventional gelatin capsules also have seams that create problems such as leakage and are less aesthetically pleasing. Due to the properties of action of the active ingredients of the present invention, Applicants believe that they contain antitussive and / or anesthetic actives, are portable, easy to use, and rapidly rupture by chewing or licking. It has been found that it is highly desirable to have a capsule composition, in which the outer shell dissolves quickly (eliminating further irritation), thereby giving the user an active formulation into the irritating area Enables quick delivery of Accordingly, it is an object of the present invention to provide improved microcapsules. Yet another object of the present invention is to provide such a composition that can treat irritation, pain and discomfort related to pharyngolaryngitis and esophagitis. It is a further object of the present invention to provide such a microcapsule composition comprising a pharmaceutically active substance that is rapidly delivered to the oral mucosa. These and other objects of the present invention will become apparent in light of the following. SUMMARY OF THE INVENTION One aspect of the present invention relates to improved microcapsules, which include an antitussive and / or an anesthetic active. All percentages and ratios used herein are by weight unless otherwise indicated. Further, all measurements were made at 25 ° C., unless otherwise specified. A detailed description essential components and optional components of the present invention the invention will be described in the paragraphs below. Capsule Shell Material The shell material of the microcapsules of the present invention can be any material suitable for ingestion and retention in the oral cavity. Suitable materials include gelatin, polyvinyl alcohol, waxes, gums, sucrose esters, and sugar candy type materials used, for example, in cough drops and mint. The outer shell material is used by being formed into any of a wide variety of shapes such as, for example, a sphere, an ellipse, a disk, a swollen rectangle, and a column. The thickness of the shell is in the range of about 30 μm to about 0.5 mm, preferably about 30 μm to about 0.3 mm. If the microcapsules are spherical, the particle size is generally in the range from about 2 mm to about 9 mm, preferably from about 3 mm to about 7 mm. The shell also has a moisture content of about 10% or more, preferably 12% or more, and most preferably 15% or more. Microcapsules made according to the present invention burst within about 45 seconds, preferably within about 35 seconds, more preferably within about 30 seconds, and most preferably within about 25 seconds, and within about 5 minutes, preferably within about 5 minutes. Dissolves within 4 minutes, most preferably about 3.5 minutes (USP Methodology XXII Method 701 "Disintegration"). Antitussives / Anesthetic Agents Antitussives suitable for use in the present invention include dextromethorphan, clofedianol, carbetapentane, caramiphen, noscapine, diphenine hydramine, codeine, hydrocodone, hydromorphone, hominoben, benzonate, and the like. Such as pharmaceutically acceptable salts and mixtures thereof are included. Oral anesthetics suitable for use include phenol, lidocaine, dyclonine, benzocaine, menthol, benzyl alcohol, salicyl alcohol and hexyl resorcinol, pharmaceutically acceptable salts thereof, and mixtures thereof. The composition of the present invention also preferably comprises at least one additional oral pharmaceutically active substance selected from the group of (a) analgesics, (b) decongestants, (c) expectorants, (d) antihistamines. Can be included. Analgesics useful in the present invention include acetaminophen, acetylsalicylic acid, indomethacin and ibuprofen, naproxen, flurbiprofen, carprofen, thiaprofenic acid, cycloprofen, ketoprofen, ketorolac, etodolac, indomethacin, sulindac, fenopro Includes optically active isomers or racemates of fen, diclofenac, piroxicam, benzidomine, nabumetone, pharmaceutically acceptable salts thereof, and mixtures thereof. Hyperemic agents prepared for use in the compositions of the present invention include pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, pharmaceutically acceptable salts thereof, and mixtures thereof. Preferred anesthetics include glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, pharmaceutically acceptable salts thereof, and mixtures thereof. All of these ingredients and their acceptable dose ranges are described in Sunshine et al., U.S. Pat.No. 4,783,465, issued Nov. 8, 1988, and Sunshine et al., U.S. Pat.No. 4,619,934, issued Oct. 28, 1986. , And are incorporated herein by reference. Bronchodilators such as, for example, terbutaline, aminophylline, epinephrine, isoprenaline, metaproterenol, bitosterol, theophylline and albuterol are also useful. A very preferred optional ingredient is caffeine. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic substrates, including inorganic and organic substrates. Salts derived from inorganic substrates include sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc, manganous, aluminum, ferric, manganese salts and the like. Salts derived from pharmaceutically acceptable organic non-toxic substrates include primary, secondary, tertiary and quaternary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. For example, triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, caffeine, precaine, N-ethylpiperidine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglyca Min, theobromine, purine, piperazine, piperidine, polyamine resin and the like. The amount of the pharmaceutical composition method of administration, the active formulation in the formulation required per dose, for example, analgesics, decongestants, cough suppressants agents, expectorants, antihistamines and / or gastrointestinal active agents It depends on percent, stability, release profile, as well as other pharmaceutical factors. Typically, about 1 mg / kg to 500 mg / kg per day, preferably about 5 mg / kg to about 300 mg / kg per day, most preferably about 5 mg / kg to about 200 mg / kg per day of a pharmaceutical composition described herein. Will be administered. This amount may be given in a single dose, or preferably in multiple (2 to 6) doses, or may be held at the release dose over the course of the treatment. Generally, the dosage of the pharmaceutical composition of the present invention for each patient will be about 1 mg / kg to about 25 mg / kg, preferably about 2 mg / kg to about 15 mg / kg, most preferably about 3 mg / kg to about 10 mg / kg. kg range. Higher doses than before may be effective, but care must be taken to avoid the corresponding side effects when with any drug. The following examples illustrate embodiments of the present invention, wherein both essential and optional ingredients are combined. These pharmaceutical agents are used in amounts from about 0.1% to about 50%. Within the shell material, the same drug can be dispersed at the same concentration. Diluent used in microcapsule core The analgesic and / or anesthetic solubilizer used in the core of the present microcapsule may be any of various substances. While water itself may constitute the entire carrier, typical liquid formulations preferably include co-solvents such as propylene glycol, corn syrup, glycerin, sorbitol solutions, and the like, which include water-insoluble formulations such as Helps solubilize and incorporate seasoning oils and the like into the composition. Thus, in general, the compositions of the present invention preferably comprise about 1 to about 70% v / v, most preferably about 5 to about 50% v / v cosolvent. Oils such as corn, olives, rapeseed, sesame, peanuts or sunflower are preferred. Other preferred substances are triglycerides such as Captex 300, and polyethylene glycols such as PEG400. They are used in an amount of about 20% to about 80%, preferably about 35% to about 70% of the total capsule weight. In addition, the present invention may optionally incorporate a cooling agent or mixture of cooling agents. Suitable cooling agents include, for example, menthol and U.S. Patent No. 4,136,163 to Watson et al., January 23, 1979; U.S. Patent No. 4,032,661 to Rowsell et al., October 28, 1980; Included are those described in U.S. Pat. No. 4,032,661. All of these documents are incorporated herein by reference. A particularly preferred cooling agent is N-ethyl-p-menthan-3-carboxamide (WS-3, supplied by Sterling Organics), which is taught in U.S. Pat. No. 4,136,163, incorporated herein by reference. Have been. Another particularly preferred cooling agent is 3-1-menthoxypropane 1,2-diol (TK-10 supplied by Takasago Perfumery Co., Ltd., Tokyo, Japan). This material is described in detail in Amano et al., U.S. Pat. No. 4,459,425, Jul. 10, 1984, which is incorporated herein by reference. Other optional ingredients well known in the pharmacist art, such as natural or artificial sweeteners, flavorings, and coloring agents to provide delicious and tasting end products, may also be used to prolong and increase shelf life. Oxidizing agents, such as butylated hydroxyanisole or butylated hydroxytoluene, and preservatives, such as methyl or propylparaben or sodium benzoate, may be included in amounts commonly known for these formulations. Additional Drugs Used Adaptably in the Capsule Core The microcapsule core of the present invention can include any of a number of additional materials to provide added efficacy and / or sensory perception. Such agents may include flavoring agents such as thymol, eucalyptol, menthol, methyl salicylate, or mansacchin. These drugs contain about .5 of the total capsule weight. It is used in an amount of 1% to about 25%, preferably about 5% to about 15%. In addition, various sweetening agents such as sugar, corn syrup, saccharin or aspartame may be included in the core. These drugs contain about .5 of the total capsule weight. 1% to about 5%, preferably about. It is used in an amount from 35% to about 1.5%. Manufacturing Method The capsule of the present invention can be manufactured using various techniques. In the following examples, certain methods are disclosed. INDUSTRIAL APPLICATION The capsule of the present invention is used by placing the capsule in the mouth, where it ruptures rapidly upon chewing or licking, where the outer shell dissolves quickly (further Irritation is eliminated), which provides the user with rapid delivery of the active ingredient to the area of irritation. The following examples further describe and demonstrate preferred embodiments within the scope of the present invention. The examples are given for illustrative purposes only and are not to be construed as illustrating the limitations of the invention. Many modifications thereof are possible without departing from the spirit and scope of the invention. Examples 1-5 The following compositions / capsules are representative of the present invention. 1) Captex 300 is a triglyceride supplied by Capitol City Product, Colombus, Ohio. 2) This amount includes in the gelatin shell and in the core. The composition is made by mixing the components of the core in one container and the components of the shell in another container. The outer shell material is heated to obtain a liquid medium. The core and shell material are then separately pumped to two or three fluid nozzles immersed in an organic carrier medium. The formed capsule is cooled and hardened. It is then dried and separated for further handling. In the composition, any of a wide variety of other shell materials, optional pharmaceutically active agents, sweeteners and other ingredients may be used in place of or in combination with the ingredients listed above.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/535 A61K 31/535 (72) Inventor Apson, James Grigg Springdale, Springfield, Pike, Ohio, United States of America 11268 (72) ) Inventor Russell, Carmelita Macklin 607, Vinsnes, Cincinnati, Ohio, USA

Claims (1)

[Claims]   1. Used for the treatment of cough and / or sore throat, suitable for oral and digestive use Microcapsules,   a) An outer shell having a wall thickness of 30 μm to 0.5 mm, wherein the outer shell has a thickness of 10% or less. An outer shell having an upper moisture content;   b) an oral physician selected from the group consisting of antitussives and anesthetics and mixtures thereof A core composition comprising a pharmaceutically active substance;   Microcapsules containing.   2. The microcapsule according to claim 1, wherein the shell material is gelatin.   3. Preferably, the microcapsules burst within 45 seconds and dissolve within 5 minutes. 3. The microcaps according to claim 1, wherein the microcapsules burst within 35 seconds and dissolve within 4 minutes. Puser.   4. The antitussive is dextromethorphan, clofedianol, carbeta. Pentane, caramiphen, noscapine, diphenhydramine, codeine, hydro Codon, hydromorphone, hominoben, benzonate, their pharmaceutically acceptable And salts selected from the group consisting of possible salts and mixtures thereof. Oral antitussives: phenol, lidocaine, dyclonine, benzocaine, menthol , Benidyl alcohol, salicyl alcohol and hexyl resorcinol, Selected from the group consisting of pharmaceutically acceptable salts thereof, and mixtures thereof. The microcapsule according to any one of claims 1 to 3, wherein   5. 5. The outer shell has a wall thickness of 30 to 0.3 [mu] m. The microcapsule according to any one of the above.   6. 6. The method of claim 1, wherein said shell has a water level of greater than 12%. The microcapsule according to claim 1.   7. The microcapsules are spherical, having a diameter of 2 to 9 mm. The microcapsule according to any one of claims 1 to 6.   8. Analgesics, decongestants, expectorants and antihistamines and mixtures thereof 8. The method according to claim 1, further comprising a pharmaceutically active substance selected from the group consisting of: The microcapsule according to claim 1,   9. 2. The microcapsule is made using three fluid nozzles. The microcapsule according to claim 8.