MXPA97003317A - Procedure for the preparation of medicated demascar rubber provided of a pleasant flavorindependent of the active agent incorporated in lami - Google Patents

Abstract

The present invention relates to a process for the preparation of medicated chewing gum, having a pleasant taste independent of one or more active agents incorporated in chewing gum, the process involves the formation of a cyclodextrin inclusion complex containing the active agent (s) that is dried and mixed with a granulated gum base without adding water or other solvents, the procedure is carried out under controlled temperature and humidity and the mixed components are cold pressed to produce a rubber product end

Description

PROCEDURE FOR THE PREPARATION OF MEDICATED MASK RUBBER PROVIDED WITH A PLEASANT INDEPENDENT FLAVOR OF THE ACTIVE AGENT INCORPORATED IN I .fl SAME CflflFQ DE Lñ INVENCIÓN The present invention relates to a process for the preparation of medicated chewing gum containing an active agent for immediate release. The gum has a pleasant taste, independently of any unpleasant organoleptic characteristics of the active agent. The novel process employed in the present invention is carried out in the absence of added organic solvents and water and under controlled temperature and humidity to protect the active agents sensitive against degradation.

BACKGROUND OF 1 FL INVFNCTON Attempts have been made to incorporate active pharmaceutical agents in chewing gum as a means of admixing the active agent into the material. Traditionally, those efforts have employed common chewing gum production techniques where a chewing gum is heated until it becomes a viscous or fluid mass. Additional components (such as flavors or active ingredients) are then mixed in the gum base. Finally, the mixture is cooled, pressed and cut to produce the final product. Alternatively, the various components are mixed in a rubber suspension which is coagulated before being pressed into the final product form. However, many pharmaceutically active agents have unpleasant taste or odor characteristics that are too evident when mixed with the gum by the above method, resulting in unpleasant chewing gum products. Many active agents tend to irritate mucous membranes. Other pharmaceutically active agents degrade rapidly, making them impractical for inclusion in chewing gum. Another problem with the known methods is that the gum base heats to a fluid mass to facilitate the mixing of other ingredients. Such elevated temperatures can cause degradation of heat sensitive compounds, including active agents and flavors. Attempts by the prior art to overcome such difficulties include the following: to avoid degradation of the active agents, the chewing go was cold produced by direct compression of the ingredients; to obtain the ability to retard or control the rate of release of active agents, the active agents were formulated in microcapsules. However, microcapsulation technology is complex and very expensive often resulting in delayed release products. Therefore, it is not well adapted for drugs for which rapid absorption through the oral mucous membranes is necessary or desirable. In addition, known procedures for medicated gum preparations often use organic solvents to dissolve the active agents. It is well known that these organic solvents are difficult to remove from the final product and may present certain health risks even when minimal quantities remain in the inal dose form. In addition, the use of organic solvents in connection with industrial processes is becoming less and less common due to health and environmental considerations (e.g., risks in terms of personnel exposure and problems to effect the proper disposal of residual solvents). Water has also been used in goat preparations, but it is difficult to remove, especially at the relatively low temperatures that are desirable for go to chew production. The heating of the mass of go to to eliminate the water is not advisable, since the rubber will become more sticky what makes the handling difficult and interferes with the production is iautornatizada or totally automated on a large scale. : > Therefore, the problems in making a medicated chewing gum produced by direct compression, with immediate or rapid release of the active agent and efficient masking of unpleasant organoleptic characteristics of the active agents, remains unresolved. The properties of ciclodextpna in the formation of inclusion complexes have been recognized and some of the difficulties mentioned above are solved by applying these techniques. It was found that certain compounds could be included within the cyclodextrins and then mixed in a base of go to low production methods of mascartradicionales gum. The compounds were then released during chewing. See, for example, U.S. Patent No. 5,165,943 to Patel et al. Although these methods helped to mask the unpleasant taste of certain compounds and reduce degradation, there were still significant disadvantages. Water and stickiness <; - Even the problems, and methods known in the art do not face the temperature sensitivity of certain active agents.

BRIEF DESCRIPTION OF THE INVENTION In view of the deficiencies of the above methods for producing medicated chewing gum containing active agents, the present method was developed to overcome these various disadvantages and provide a novel method for producing medicated chewing gum containing inclusion complexes of active agents enclosed in cyclodext quarrel. This procedure avoids the use of organic solvents and water and is especially adapted for use with heat sensitive active agents. In addition, the process of this invention avoids the heated rubber base and rubber suspensions coldly known in the art. These objectives and others are achieved by cooling the gum base by grinding it into granules that are then mixed dry with optional excipients in the absence of water and solvents at controlled temperature and humidity. These objectives are also achieved by cold pressing the mixed rubber and the components in the final tablet form.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of medicated chewing gum containing inclusion complexes of active agent enclosed in cyclodextrin in which the components are dry mixed under controlled temperature and humidity and the resulting gum mixture is pressed in cold under similar controlled temperature and humidity. As used herein, "medicated" chewing gum means chewing gum containing one or more of the following active agents: a physiologically active ingredient, nutritional supplement or pharmaceutically active ingredient. Non-limiting examples of active agents are given below. The cyclodextrins are cyclic-1,4-cyclic iron that has six to twelve glucose units. The branched cyclodextrains with bound glucose linked by a-1, 5-glycosidic bonds also exist. Cycloderms are formed enzymatically from starch through the action of glycosyl transferase produced by certain microorganisms, β-cyclodextrins, having seven glucose units and a molecular weight of 1135, is preferred for use in the present invention. Cyclodext preparation is well known in the art. The crystalline, colorless, commercially available form of ß-cyclodextrin with purity greater than 98% is most preferred. Active agents suitable for use in the medicated chewing gum disclosed herein include, but are not limited to vi-t amines, and particularly 1-ascorbic acid (vitamin O; analgesics and particulately acetabulin inophen (flPAP) and ibuprofen antihistamines, and particularly dirnenhydrinate, antibacterial agents, and particularly cyclohexidine diacetate, chelated minerals and particularly chromium polycholine, tournament agents, and particularly ginseng, circulatory agents and particulate ginkgo biloba extracts, oral deodorants, and particularly tea extracts. and of vegetables and nicotine, the rosolubles and liposoluble active agents are encapsulated within cyclodextrins and are released in the mouth by salivary lases.For inclusion in the cyclodextrin, the active agents are stabilized and become more soluble. well-developed technology used to generate inclusion complexes is simpler and more advantageous in relation to n the techniques necessary for micro-encapsulation. In addition, through the use of inclusion complexes, the bio-identity of the active agents encapsulated in ciclodextpna is accentuated. In addition, this technique provides excellent means to mask the unpleasant organoleptic characteristics of many active agents. Additional details are provided in the Italian patent application MI 95 / A 000180 of Testa et al., Filed on February 2, 1995, the description of which is hereby incorporated by reference in its entirety (in case of conflict, the controls herein I described you a). The procedure for the preparation of the medicated chewing gum is described later in its general form by way of example. Nevertheless, it is possible to effect numerous alternative variations, as will be obvious to one skilled in the art. The inclusion complex can be prepared by a variety of means known to one skilled in the art. Typically, an amount of cyclodextrin is placed in an appropriate container with an appropriate amount, eg, one to two parts of distilled water. The suspension is mixed, v. gr. , with a mechanical agitator for 10-15 minutes until complete furnace. Then an equivalent amount of active agent is added (sufficient to be included in inclusion complexes of cyclodextrin). After the active agent is added, the suspension is mixed for the amount of time necessary to complete the inclusion of the active agent in the cyclodextrin, typically 3 to 5 hours. The inclusion complex suspension is subsequently dried. The water can be re-thrown through the vacuum, or this can also be achieved through the use of a rotary stirrer or in an oven, where a temperature of less than 50 ° C is maintained. The resulting solid is ground to 50-500 mesh, resulting in a dried powder form of inclusion complex. The inclusion complex is eventually added to the gum base after the gum base has been processed as explained below. The gum base used in the present invention can be any suitable gum base known in the art, including natural gum such as chewing gum, jelutong, gutta percha and coronary gum. The base of go a is prepared by cooling natural rubber to -10 ° C and grinding it. Guar gum and glycetate are preferably added so that the resulting rubber mixture typically consists of a ratio of 99 to 0.9 to 0.1 by weight (gum n al to: guar gum: gilcerin). One or more known chewing gum excipients may be added to the gum base, before or after being combined with the inclusion complex. These excipients include, but are not limited to, sweeteners, flavoring agents, and compression adjuvants. Sweeteners are generally carbohydrates, particularly sucrose and glucose. If non-generative products are desired, mannitol, sorbitol, glycine and other non-cavity generating excipients can be used. For such non-cavity-generating products, sweeteners such as aspartame, sulfarnate, <may be used.; 1e cyclohexyl, saccharine, acesulfarne, stevioside and glycyrrhizin ammonium nato. Sapozant agents may also be added to the gum base. Suitable sabotagents for use in the present invention include, but are not limited to, essential oils and synthetic flavors such as citrus oils, fruit essences, peppermint oil, peppermint oil, clove oil, gaultepa oil, anise and similar. This invention also contemplates artificial flavors known to those skilled in the art. Compression aids can also be added. These compounds facilitate the compression of the gum in tablets. Suitable compression aids include, but are not limited to, silicon dioxide, stearate. magnesium, calcium stearate, behémco acid, talcum and similar substances can be used and are often essential to limit the tendency of rubber tablets to stick to presses. 5 The powder containing the inclusion complexes of cyclodextrin and active agent is subsequently mixed with the gum base processed in the absence of water or organic solvents. The relationship between the inclusion complex and the go to processed base can vary widely (depending on the The amount of active agent that should be supplied per gum tablet, the following scale being useful for most applications. 110 inclusion complex 150 650 < processed gum base < The process of the present invention is improved by maintaining controlled temperature and humidity. The mixture of the other components with the gum base is carried out at a temperature below 20 ° C, preferably below 18 ° C and relative humidity below 50%. It should be noted «lú la The temperature should not be too high to interfere with the handling of the medicated gum and the rattling process. In this way, preferably the temperature should be above 10-12 ° C. The final mixture is subsequently transferred to a ? suitable tapping machine «Ja for the production of the final rubber product« che che. The rattle machine is also maintained at temperatures below 20 ° C and preferably below 18 ° C, and the relative ambient humidity is kept below 50% but typically at 40% or more (always below 50%). By way of example, an 18-die machine, such as Ronchi RÜ18, (Fratelli RONCHI S.p.A., Cinsello Balsamo, Italy) can produce -50,000 units / hour by the method described above. The final tablets typically weigh between 1.5-3.5 g and when chewed form a gummy lump without any unpleasant taste or mucosal irritation. The method according to the present invention is described more fully in the following examples, which are provided by way of illustration only and are not intended to limit the scope of the invention in any way.

EXAMPLES EXAMPLE NO. 1 A suspension of 135 g of ß ~ c? Clodextpna and 20 g of 1-ascorbic acid (vitamin C) in 300 ml of distilled water is placed in a glass flask fitted with a mechanical stirrer and mixed for 5 hours at room temperature (15-? 5 ° C). After stirring, vacuum is applied (10-30 m Hg) and the water is removed by progressively heating to 50 ° C. The dry product is sieved through 50 meshes.

A portion of this product (140.5 g) is mixed with 68 g of dry gum base (free of solvents) previously prepared as follows: natural gum is cooled to -10 ° C, milled and diluted with 0.9% guar gum and 0.1 g. % gillin (w / w). Everything is sifted through 50 meshes. The mixture obtained weighs 208. 5 grams. Two grams of rnanitol, 2 g of glycol, 3 g of syloid 244 (GROCE G. .b.H D-67545 orrns in der Hollanbacke) and 1 g of behenic acid are added. Everything (216 g) is mixed for 15 minutes and sieved through 200 meshes. Finally add 3 g of aspartame (artificial sweetener), 5.5 g of orange oil and 1 g of magnesium stearate (compression allyvant). From this 226 g of granules are obtained which are compressed in a rotary press RONCHI R18. You get ninety -tabletas. The weight of the tablets is 2.5 g. Each tablet contains 200 mg of vitamin C.

AXIS? PLQ NQ. 2 A suspension of 105 g of ciclodextpna and 15 g of acetaminophen (APAP) in 250 ml of distilled water is prepared in a glass flask equipped with a mechanical stirrer and mixed for three hours at 25 ° C. After this time vacuum is applied (15-20 mm Hg) and the water is removed by gradually heating to 50 ° C (bath temperature). The product obtained is sieved through 50 meshes.

A pair of this product (108 g) is mixed with 72 g of gum base itself, which is prepared by cooling the base gum (Jelutong) to -10 ° C, grinding it, adding later 0. 9% guar gum and 0.1% glycepne (w / w). Everything is sifted through 50 meshes. The total mixture weighs 180 g. 5 g of sucrose, 3 g of syloid 224 and 1 g of behemoth acid are added to the gum base. Everything is mixed in a mixer (K calse mixer) at a temperature of at least 20 ° C. Finally, 5 g of aspartame, 3.5 g of grapefruit essence and 1 gram of magnesium stearate are added. The components are mixed in a stirrer for 5 minutes and sieved through 50 meshes. 226 g of granules are obtained and compressed in a rotary press RONCHI obtaining 90 tablets (theoretical production). The weight of the tablets is 2.5 g with a content of 150 mg of APAP (average weight) EXAMPLE NO. 3 A suspension of 140 g of β-cyclodextrin and 20.6 g of ibuprofen in 200 ml of water is prepared: the mixture is stirred for 5 hours at 20 ° C (ambient temperature). The suspension is transferred to a glass tray, dried in a dry vacuum and heated to 50 ° C. Theoretical production: 161 g. 144.9 g are taken out and mixed with 75.1 g of gum base prepared by cooling the natural gum (Je lut ong) to -1 0 ° 0, in "Jola in a mechanical mill and adding" l in " 0.9% «je guar gum and U.1%« Je glicer-ina (w / w). The components of the gum base are mixed in a stirrer and passed through "Je un -tamiz en 50 mesllas. The total mixture weighs 220 g. To the mixture are added 5 g "Je mamtol, 4 g of sylloid 224 and 1 g" Behenic acid. This is mixed in a stirrer - for 20 minutes at a temperature of at least 20 ° C. Finally, 10 g of aspartame, 7.5 g of mint essence and 2.5 g of magnesium stearate are added to the same stirrer. The mixture is mixed for 5 minutes, passed through a screen (50 mesh) and the final granules (249 g) are compressed in a rotary press. From this, 90 tablets (theoretically) weighing 2,750 g with a content of 200 mg of ibuprofen are obtained.

EXAMPLE NQ.

A suspension was prepared which consisted of 100 g of β-c ?clo «Jextpnas and 25 g of« Junenhydrinate (antihistarninic product) in 150 ml of distilled water: the mixture was stirred for 5 hours at 20 ° C (room temperature). ). The suspension was transferred to a glass tray, placed in a vacuum dryer and heated to 50 ° C until the total water evaporation occurred (constant weight). The granules were sieved through 50 meshes. Theoretical production: 125 9- 114.5 g are mixed and mixed with 650 g of gum base prepared by cooling the natural gum (Jelutong) to -10 ° C, grinding it in a mechanical mill and adding 0.9% guar gum and 0.1% giicerma (p / p). They are mixed «Jos in a stirrer and passed through a sieve in 50 meshes. The final mixture has a weight of 764.5 g. To the mixture are added 350 g of mannitol, 300 g of glycol, 45 g of sylloid 254 and 30 g of benzoic acid. The components are mixed in a stirrer for 20 minutes. The ambient temperature must be less than 20 ° C. 75.5 g of aspartame, 80 g of peppermint flavor and 25 g of magnesium stearate are added to the same stirrer. The components are subsequently labeled for 5 minutes, through a sieve in 50 mesh and compressed in a RONCHI rotary press. The theoretical production is 1670 g. 900 tablets of 1.85 g containing 25 mg of dirnehydrate are obtained.

Claims (1)

1. NNVFDOD OF THE INVENTION CLAIMS 1. - A process for the preparation of medicated chewing gum, which has a pleasant taste independent of one or more active agents incorporated therein, which complies "Je: a) to form an inclusion complex of one or more agents with cyan. clodextpna, b) drying the inclusion complexes of step (a), c) mixing the dry inclusion complexes with a gum base and suitable excipients in the absence of water or organic solvents added under controlled temperature and humidity, and d) cold pressing of the mixture of the step) c) ba or temperature and h? me «controlled to produce a tablet« He chewing gum-medicated. ? . - The method according to claim 1, further characterized in that the cold pressing is carried out at a temperature below 20 ° and relative humidity of 50% or less. 3. The process according to claim 1, further characterized in that the mixing of the dry inclusion complexes with the base of the rubber and excipients is carried out at a temperature below 20 ° and relative humidity of 50. % or less. 4. The method according to claim 1, further characterized in that the crystalline β-cyclodextrin with greater purity "Je 98%" is used. 5. The method according to claim 1, further characterized in that the inclusion of the active agent in the cyclodextrin is carried out by suspending the cyclodextrin in distilled water, homogenizing the suspension by agitation, adding the active agent, mixing until the inclusion is completed, removing the water mechanically or heating and grinding the resulting powder to obtain a dry mixture. 6. The process according to claim 1, further characterized in that the gum base comprises natural gum, guar gum and glycepne. 7. The process according to claim 1, further characterized in that the excipients comprise carbohydrates. 8. The process according to claim 7, characterized by "Jomas" because the excipients comprise at least one of glucose and sucrose. 9. The method according to claim 1, further characterized in that the excipients include non-cavity generating compounds. 10. The process according to claim 1, further characterized in that the excipients include sweeteners. 11. The process of conforming with the claim 1, further characterized in that the non-cavity generating compounds include at least one of maltol, sorbitan and glycine. 12. The process according to claim 1, further characterized in that the sweeteners include at least one of aspartame, cyclohexyl sulfate, saccharin, acesulfame-1, glycyrrhizinate and ethersteriod. 13. The method according to claim 1, further characterized in that the excipients include compression adjuvants. 14. The process according to claim 1, further characterized in that the compression adjuvants include at least one of silicon dioxide, magnesium stearate, calcium stearate, behenic acid. 15. The process according to claim 1, further characterized in that the active agent comprises ascorbic acid (vitamin O. 16.- The process according to claim 1, further characterized in that the active agent comprises dimension i of n. 17. The method according to claim 1, further characterized in that the active agent comprises ibupro f 18. The method according to claim 1, further characterized in that the active agent comprises "Je di enhi drato. 19. - 111 method according to claim 1, further characterized in that the active agent comprises "chlorhexidine liacetate. 20. The method according to claim 1, further characterized in that the active agent comprises nicotine. 21. The process according to claim 1, further characterized in that the active agent comprises i nsen. 22. The process according to claim 1, further characterized in that the active agent comprises gml-O biloba extract. 23. The process according to claim 1, further characterized in that the active agent comprises tea extract. 24. The process according to claim 1, further characterized in that the active agent comprises chromium polypi chlorate. 25. A tablet of medicated chewing gum produced in accordance with the method of claim 1. 26. A tablet "Gum" medicated chewing produced according to the method of claim 4. 27.- A medicated chewing gum tablet produced in accordance with the procedure of claim 6. 28.- A tablet and medicated chewing gum produced "In accordance with the method of claim 7. 29. - A rubber tablet for medicated chewing produced in accordance with the method of claim 8. 30.- A medicated chewing gum tablet produced in accordance with the method of claim 9. 31.- A rubber tablet medicated chewing gum produced in accordance with the procedure «Je claim 10. 32.- A medicated chewing gum tablet produced in accordance with the procedure« Je claim 11. 33.- A tablet < Medicated chewing gum produced in accordance with the method of claim 12. 34.- A tablet of medicated chewing gum produced in accordance with the method of claim 13. 35.- A medicated chewing gum tablet produced in accordance with the procedure of claim 14. 36.- A tablet «Je gum« Je chewing medicated produced The method according to claim 15. 37. A medicated chewing gum tablet produced according to the method of claim 16. 38. A tablet of chewing gum rned? Ca < The product produced in accordance with the procedure "Je claim 17. 39.- A medicated chewing gum tablet produced in accordance with the method of claim 18. 40.- A gummed tablet" medicated chewing gum produced in accordance with the The method of claim 19. 41.- A "chewing gum" tablet produced in accordance with the method of claim 20. 42. - A medicated chewing gum tablet produced in accordance with the method of claim 21. 43.- A tablet of medicated chewing gum produced in accordance with the method of claim 22. 44.- A gum tablet medicated chew produced in accordance with the process of claim 23. 45.- A tablet of medicated chewing gum produced in accordance with the procedure of the rejection 24. RF SUMMARY OF THE INVENTION A process for the preparation of medicated chewing gum, which has a pleasant taste independent of one or more active agents incorporated in chewing gum; the process involves the formation of a cyclodextrin inclusion complex containing the active agent (s) that is dried and mixed with a granulated gum base without adding water or other solvents; the process is carried out under controlled temperature and humidity and the mixed components are cold-pressed to produce a final gum product. 33 / JN / rnrnrn * P96 / 440