KR100612520B1 - Highly plastic granules for making fast melting tablets - Google Patents

Abstract

Rapid melt pharmaceutical tablets include porous plastic materials, water penetration enhancers, and binders. One or more drugs may be incorporated into the formulation at different stages of the process to obtain a pharmaceutically active tablet. The preparation method of such a pharmaceutical tablet includes mixing a porous plastic material, a water penetration enhancer, and a binder to form highly plastic granules and compressing the same into tablets. The resulting tablets dissolve rapidly in the mouth and do not crumble well and have good hardness. This tablet is particularly useful for those who have difficulty swallowing conventional pills.

Rapid melting tablets, binders, water penetration enhancers, high calcined granules, dysphagia

Description

Highly plastic granules for making fast melting tablets

The present invention relates to highly plastic granules for the production of rapid melting tablets.

The term "difficulty in swallowing" to describe swallowing difficulties is common in all ages. According to one study, people with dysphagia make up about 35% of the general population and make up 30-40% of older patients in the facility, as well as 18-22% of all people in long-term care facilities. [Reference. See, eg, Sastry, S. et al . , Pharm. Sci. & Tech. Today 3: 138-145, 2000]. Common complaints related to difficulty swallowing tablets are tablet size, surface, shape, and taste (in frequency order of complaints). Elderly patients and pediatric patients, as well as traveling patients who have difficulty getting water, prefer a formulation that can be taken without water and is easily swallowed. Other studies also indicate that about 50% of the population suffers from the difficulty of swallowing tablets [Seager, H., J. Pharm. Pharmacol. 50: 375-382, 1998]. Solid formulations that can be disintegrated, dissolved or suspended by saliva in the mouth and can be easily swallowed can provide important benefits for pediatric patients or elderly patients as well as other patients who prefer an easy swallowing formulation.

Over the last decade, rapid dissolving purification techniques have been receiving considerable attention, allowing tablets to break down in the mouth without additional water absorption. This novel rapid dissolving technology is also known as rapid dispersing, rapid dissolving, rapid melting and / or rapid disintegrating tablets. Quick-dissolving tablets often break down into smaller granules and slowly dissolve in the mouth. The dissolution time of the fast-dissolving tablets varies from seconds to minutes, depending on the formulation and the size of the tablet. Quick-dissolving tablets provide the patient with the advantage of replacing traditional tablets or capsules that must be administered with water, and liquid formulations that are traditionally bulky and less precise. Rapid dissolution tablets are especially needed for older people, children and many people with swallowing disorders.

As used herein, the term “fast melt tablet” refers to a novel formulation that produces a paste-like structure in which solid tablets can be broken down into small particles and easily swallowed or completely dissolved in the mouth. Because the terms “quickly soluble tablet” and “quickly disintegrating tablet” are widely used in the literature, these terms refer to background features of the present invention and other techniques herein. As used herein, "FDT" refers to "quickly soluble tablets" or "quickly disintegrating tablets".

Method for preparing rapid dissolving tablets

Several techniques for making commercially available FDTs have been used for some time. For example, ZYDIS ^® (Cardinal Health; Dublin, Ohio), ORASOLV ^® and DURASOLV ^® (Cima Labs, Inc .; Eden Prairie, Minn.) And WOWTAB ^® (Yamanouchi Pharma Technologies, Inc .; Palo Alto, Canada) The technology was used to manufacture products in the US market. Although these techniques meet some of the specific requirements for FDT, none of them have all of the desired characteristics. For example, to maximize the porous structure of tablets, current FDT technology uses suitable disintegrants and / or highly water soluble excipients in tablet formulations. Currently available techniques are disclosed in the literature. See, eg, Sastry, S. supra; Habib, W. et al . , J. Pharm. Pharmacol . 50: 375-382, 1998; And Bogner, R., et al., US Pharmacist 27: 34-43, 2002]. These techniques are often classified as freeze-drying, molding or compression processes, depending on the process used to make the FDT.

Freeze-drying process : Freeze-drying (freeze-drying) is a process in which solvent is removed from a structure-forming excipient containing a frozen drug solution or frozen drug suspension. The resulting tablets often have a porous and flexible structure that allows for very light and rapid dissolution. When placed on the tongue, the unit dissolves almost immediately to release the incorporated drug. The whole freeze drying process is carried out at non- elevated temperatures, thus eliminating the adverse thermal effects that can affect drug stability during the process. When stored dry, the formulations have relatively few stability issues over their shelf life. ZYDIS technology is described in US Pat. No. 4,371,516 to Gregory et al. And US Pat. No. 5,738,875 to Jarwood et al. Freeze drying is a relatively expensive manufacturing process and the final formulation is so weak that it lacks physical resistance in standard blister packaging. In addition, the method cannot accommodate high amounts of active drug. In addition, the water soluble drug may form a eutectic mixture that cannot be suitably frozen to form the rigid structure necessary to support itself after the solvent is removed, which may cause the collapse of the freeze dried cake, thereby making the water soluble drug Administration is usually limited to 60 mg [Seager, H., homologous].

Molding Process : The main component of the molded tablet is typically a water soluble component. The powder mixture is wetted with a solvent (often water or ethanol) and then the mixture is put into a molding plate to compact to form a wet mass (compression molding). This wet mass is shaped into tablets at a pressure lower than the pressure used for conventional tablet compression. The solvent is evaporated by air-drying. Since shaped tablets are much less dense than compressed tablets, more porous structures result in improved dissolution. To improve rapid dissolution, the powder blend must pass through a very fine screen. Recently, shaped forms are prepared either directly from the molten matrix (heat molding) in which the drug is dissolved or dispersed, or by evaporating the solvent from the drug solution or suspension at ambient pressure (not vacuum lyophilization) [Dobetti, L ., Pharmaceutical Technology North America, Suppl. (Drug Delivery) , 44-50, 2001. Since the main component in the dispersion matrix is generally made of water-soluble sugars, the shaped tablets disintegrate more quickly to provide an improved taste. Unfortunately, shaped tablets typically do not have very high mechanical strength. Reference. U.S. Patent 5,082,667, issued to Van Skoke. The shaped tablets are likely to erode or break while handling tablets and when opening blister pockets. Using unconventional apparatus and / or multi-step processes, FDTs with suitable mechanical strength and good disintegration capability were prepared by molding techniques. However, the use of unusual manufacturing methods requires more machine investment. Compared to FDT prepared by freeze-drying, shaped tablets can be made on a simpler and more effective industrial scale, but the disintegration time is not comparable to the disintegration time of the lyophilized form.

Compression Process : Conventional tablet compression methods for the preparation of fast dissolving tablets can be very interesting because of the low manufacturing costs and ease of technology transfer. However, tablet compression is designed to prepare conventional tablets. When preparing conventional tablets, maintaining the high porosity of the tablets is not a major concern. High compressive forces are used to ensure tablet strength. Many techniques have been tried to achieve high porosity and suitable tablet strength using tablet compression. The compression process is the most widely used for making FDTs. Three widely used methods are granulation methods, special excipient methods and compression and subsequent processing methods. Since the present invention relates to a compression method, the above-described method will be described in more detail later.

Granulation Methods : All obvious methods used to obtain granules for producing FDT are wet granulation, dry granulation, spray drying and flash heating methods. These methods are briefly described below.

a. Wet granulation

U. S. Patent No. 6,149, 938 to Bonadeo et al. Discloses a method for preparing rapidly disintegrating orally soluble tablets by wet granulation in a fluidized bed. The inventors claim that similar rapid disintegration times can be achieved by using blowing agents provided in tablets at less than 5%. They also found that rapid disintegration times can be achieved by using only the acid component of the foamable material. They suggest the use of polyalcohols (such as mannitol, xylitol, sorbitol, maltitol, erythritol and lactitol), 1-30% of edible acid and active ingredient as a dry mixture. The mixture was wet granulated with an aqueous solution of a water soluble or water dispersible polymer (such as poly (ethylene glycol), carrageenan, and ethylcellulose) consisting of 1-10% of the final weight granules in the fluidized bed. Granules with high porosity and low apparent density were obtained, and tablets made from these granules were reported to have a rapid disintegration time of 3 to 30 seconds in saliva.

U. S. Patent No. 6,316, 029 to Zyne et al. Presents a rapidly disintegrating tablet for an active ingredient with poor solubility. First, nanoparticles are formed by mechanical polishing, precipitation or other suitable size reduction process. These nanoparticles of less than 2,000 nm were attached to surface stabilizers such as nonionic and ionic surfactants. The particles were granulated using a fluidized bed and using at least one pharmaceutically acceptable water soluble or water dispersible excipient; These granules were made into tablets. These tablets disintegrate or dissolve completely in less than 3 minutes.

b. Dry granulation

U. S. Patent No. 5,939, 091 to Eoga et al. Discloses a process for preparing FDT by dry granulation. High density alkaline earth metal salts and water soluble carbohydrates do not provide rapid disintegration and a pleasant mouth feel. Low density alkaline earth metal salts and water soluble carbohydrates can be difficult to compact resulting in inadequate content uniformity. Therefore, the low density alkaline earth metal salts or water soluble carbohydrates were pre-compressed and the resulting granules were compressed to make tablets that can be quickly dissolved. In this process, the powdery material at a density of 0.2 to 0.55 g / ml was pre-compressed and increased to a density of 0.4 to 0.75 g / ml by applying a force in the speed range of about 1.0 kN to about 9.0 kN / cm. The resulting granules were compressed into tablets.

c. Spray drying

Spray drying provides the fastest and most economical way to remove the solvent to produce porous and calcined fine powders. U. S. Patent No. 6,207, 199 to Allen et al. Provides a particulate support matrix for use in forming tablets that dissolve rapidly by using spray-drying techniques. The component in the particulate support matrix comprises a support consisting of two polypeptide components of the same net charge (preferably non-hydrolyzed gelatin and hydrolyzed gelatin), a bulking agent (mannitol) and a volatile agent. The mixture of the aforementioned ingredients is spray dried to obtain porous granules. By incorporation of volatiles (in most cases ethanol), the surface tension of the droplets was further reduced during spray drying and more pores and channels were produced. The solubility of the matrix was further improved (in a short time) when combined with the bulking agent. Minimal amounts of volatiles may optionally be included to enhance dissolution rate. In order to keep the tablet completely during handling, a thin coating of polymeric material may be applied to the outside. The active ingredient may be microencapsulated or nano-encapsulated to mask taste.

d. Flash heating process

Fuisz et al. Introduced shearform technology to produce FDT. The technique, as described in PCT Publication WO 95/34293 and US Pat. No. 6,048,541, uses a unique spinning mechanism to produce a cottony crystal structure very similar to cotton candy. In this process, the raw materials were simultaneously provided with centrifugal force and temperature gradient. This condition creates an internal flow which directs the flow mass out of an opening provided around the spinning head. As the mass came out of the opening, the mass was cooled to form a discontinuous fiber structure as seen in cotton candy. The spinning speed is about 3,000 to 4,000 rpm and the temperature gradient is about 180-250 ° C. Carrier materials include sugars, polysaccharides, and mixtures thereof. The prepared cotton should be recrystallized to form free flowing granules with self binding properties.

Specific excipient methods : These methods focus on selecting specific excipients, such as water insoluble calcium salts, specific disintegrating combinations, and specific sugar combinations, as the main component of the FDT.

a. Calcium salts as specific excipients

U.S. Patent 6,596,311, issued to Dobetti, discloses a formulation using insoluble inorganic excipients as a main ingredient for rapid disintegrating tablets. According to this document, the disintegration of tablets in the oral cavity depends on the amount of disintegrant and insoluble inorganic excipient used. The disintegration also depends on the relative weight ratio between the water insoluble excipient and the water soluble excipient when a water soluble excipient is used. It has also been found that in these formulations, sufficient compressive force is applied to form tablets with strong tensile strength and low degree of fracture. Disintegration rates are known not to be significantly affected by high compressive forces. Substantially water insoluble components include water insoluble excipients, water insoluble drugs (coated or uncoated), and water insoluble lubricants and sliding agents. Water insoluble excipients include insoluble inorganic salts (such as di- or tri-basic calcium phosphates) or organic fillers (such as microcrystalline cellulose).

b. Sugar-based excipients

Sugar-based excipients such as sorbitol, mannitol, dextrose, xylitol, fructose, maltose, isomalt, maltitol, lactitol, starch hydrolyzate and polydextrose are highly water soluble, sweet and satisfying in mouth. It has been widely used as a bulking agent because of its feel and good taste masking properties. Almost all formulations for rapidly dissolving tablets contain several sugar substances in their formulations (Chang, RK., Et al., Pharmaceutical Development and Technology , 24: 52-58, 2000).

Other proposals are described in US Patent (granted to Mizumoto, etc.) 5,576,014 No., 6,589,554 No. (issued to Mizumoto, etc.) and 6,465,009 No. (to grant Liu, etc.), and they relate to a so-called WOWTAB ^® technology Yamaguchi Pharma shoe tikeol companion . This technique uses a combination of low forming and high forming sugars to produce fast dissolving tablets using conventional granulation and tableting techniques. As described in the above references, the sugars are divided into high form sugars and low form sugars. Low forming sugars produce tablets with a hardness of 0-2 kg when compressing 150 mg of sugar using an 8 mm diameter die under a pressure of 10-50 kg / cm ² . Examples of hypoplastic sugars include lactose, mannitol, glucose, sucrose and xylitol. Highly forming sugars produce tablets having a hardness of at least 2 kg when prepared under the same conditions. Typical hyperplastic saccharides consist of maltose, maltitol, sorbitol and oligosaccharides. When tablets are prepared by compressing only low- or high-form sugars, the desired properties such as rapid disintegration in suitable hardness and in the mouth cannot be achieved simultaneously. In addition, if the low-forming sugars and the high-forming sugars are mixed (physical mixture) before tableting, rapid disintegration and dissolution in the mouth cannot be obtained. According to the references, no single sugar could produce a tablet that satisfies both high strength and rapid disintegration properties. For this reason, the low-forming sugar was granulated using the high-forming sugar as a binder. Low forming sugars were used as the main ingredient. The mixing ratio of the high-forming sugar and the low-forming sugar is in the range of 2: 20% by weight, preferably 5 :: 10% by weight. In these systems up to 50% (w / w) of the tablet weight may be the active ingredient. Tablets made by compacting the granules are claimed to exhibit rapid disintegration and dissolution when placed in the proper hardness and mouth.

c. Disintegrant

Most rapid dissolving tablet formulations use some type of disintegrant. Some formulations use some of the effervescent materials as disintegrants, while others use combinations of disintegrants. An overview of the different types of non-volatile disintegrants used in the pharmaceutical art is described in Dobetti (US Pat. No. 6,596,311).

USA, as described in Patent No. 5,464,632 (issued to Cousin, etc.), La see storage FLASHTAB's ^® technology professionals papam (France) produces a tablet by compression of a granular excipients. Excipients used in this technique include two groups of components. One group is a disintegrant, such as carboxymethylcellulose or insoluble reticulated polyvinylpyrrolidone. Another group is swelling agents such as carboxymethylcellulose, starch, modified starch, carboxymethylated starch, microcrystalline cellulose and possibly directly compressible sugars. Mixtures of excipients were prepared by dry or wet granulation methods. The tablets produced are known to have satisfactory physical resistance and disintegrate within 1 minute in the mouth.

U.S. Patent No. 5,178,878 (issued to Wehling, etc.) proposes to Cima Labs, Inc. ORASOLV ^® technology. This reference discloses a low pressure compression method for preparing rapid dissolving tablets using an expandable disintegrant. Volatile disintegrants are compounds that release gas upon contact with water. The most widely used effervescent disintegrant pairs often include acid sources and carbonate sources. Acid sources include citric acid, tartaric acid, malic acid, fumaric acid, adipic acid and succinic acid. Sources of carbonates include sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate. The carbon dioxide released from the reaction can provide the patient with a kind of "feeling of foam", which is a positive sensory feeling. The formulations described in this patent include effervescent disintegrants, pharmaceutical components in the form of microparticles and other excipients such as binders and non-foamable disintegrants. The amount of effervescent disintegrant is about 20-25% of the total weight of the tablet. The pharmaceutical ingredient incorporated into the tablet is in the form of fine particles. These microparticles can be prepared as microcapsules or matrix microparticles. The particulate form can also be used to mask the bad taste of the drug as well as to control the drug release properties. Due to the soft and friable nature of the ORASOLV ^® tablets, referred to as PAKSOLVE and was protective for purification to avoid damage during transport and storing purified by developing special packaging systems such as described in U.S. Patent 6,311,462 No. (to grant Amborn etc.). The DURASOLV ^® technology was also developed by the same company to provide stronger tablets for packaging in foil pouches or bottles as described in US Pat. No. 6,024,981 to Khankari et al. The main components in such formulations are non-direct compression fillers and lubricants. Very fine fillers, also known as non-direct compression fillers, are used as the main component. Materials that can be used as non-direct compression fillers are non-direct compression sugars and sugar alcohols such as dextrose, mannitol, sorbitol, lactose and sucrose. The amount of non-direct compression filler is about 60-95% of the total tablet weight.

Compression and Subsequent Processing : These methods initially produce compressed tablets at low pressure and then apply various post treatments such as sublimation, sintering and humidity treatment to make the soft tablets strong.

a. sublimation

In the sublimation technique, the high porosity essential for rapid disintegration is achieved by using volatile materials. Inert solid components such as urea, ammonium carbonate, ammonium bicarbonate, hexamethylene tetramine and camphor can be readily volatilized. When these volatiles are compressed into tablets, they can be removed through sublimation to create a porous structure. US Patent 3,855,026 to Heinemann et al. Discloses a process for preparing porous tablets by sublimation. A mixture of volatile adjuvants is prepared into a tablet and then heated to remove the adjuvant since the residual amount of adjuvant in the tablet can adversely affect the patient. Another method is shown in US Pat. No. 5,762,961 to Roser et al., Which discloses a process for preparing rapid dissolving tablets by sublimation. The ingredients in the formulations include volatile salts (such as ammonium bicarbonate, ammonium acetate and ammonium carbonate) in amounts of 30-50% (w / w) of the tablets, diluents (such as trehalose or lactose), binders and other additives do.

b. Humidity treatment

Certain sugars are known to change from an amorphous state to a crystalline state when the solution is spray dried or used as a binder solution. Further research has also revealed that when amorphous sugars are subjected to humidity and drying processes, they change to crystalline state. This change substantially improves the tablet strength.

U. S. Patent No. 6,589, 554 to Mizumoto et al. Discloses humidifying and drying drug, sugar and amorphous sugars that can be converted from the amorphous state to the crystalline state. The main action of the sugar is to dissolve in the oral cavity. The amount of sugar in the formulation can be adjusted depending on the drug content and the tablet size. Preferred sugars include lactose, glucose, trehalose, mannitol, erythritol and the like. "Amorphous sugar" refers to a sugar capable of converting the amorphous state by spray drying, freeze drying or other granulation methods. "Amorphous sugars" include glucose, lactose, maltose, sorbitol, trehalose, lactitol, fructose and the like. The crystalline form of the sugar dissolved in the solvent is sprayed onto the drug. Humidification and subsequent drying processes are used to increase tablet strength. Relative humidity is determined by the apparent critical relative humidity of the mixture of drug and amorphous sugars. The relative humidity above or equal to the critical relative humidity of the mixture is selected as the humidity condition. The advantage of using amorphous sugars is that their critical relative humidity is low so that they can absorb water even at low humidity levels. The crystalline form of the sugar is not easy to control the humidity absorption. Water absorption of the crystalline form is not sufficient to strengthen the tablet at low humidity conditions. If high humidity conditions are used, the tablets will stick to each other and cause manufacturing problems. Another advantage of using amorphous sugars is that the reaction from the amorphous state to the crystalline state is irreversible. Sugars in the crystalline state have a high critical humidity point. Fortified tablets are less affected by moisture.

U. S. Patent No. 6,465, 009 to Liu et al. Discloses a system for preparing rapid dissolving tablets by humidity treatment. Water-soluble polymers are used as the binder solution. The method comprises the following steps: granulating the active ingredient and other excipients such as mannitol, lactose, glucose, sucrose and lactitol using a water soluble polymer as the binder solution; Compacting the granules into tablets; Humidifying the tablet at a relative humidity of about 50-100%; And drying the tablet. It is known that the tablets have a hardness of about 0.5 to 12.0 kilo pounds and in vivo disintegration times of about 1 to 40 seconds.

As disclosed in US Pat. No. 6,316,026 to Tatara et al., Rapid dissolving tablets may be prepared by an apparatus for handling fragile tablets prior to wet treatment and water treatment. The active ingredient and at least one water soluble sugar were compressed at a pressure of 0.01 to 0.2 ton / cm ² . The tablets are wet and dried to produce 20-40% porosity. The active ingredient in the formulation should preferably be less than 30%. Useful sugars in the formulation include erythritol, xylitol and mannitol. Tablet manufacturing apparatus include a rotary punch press, a relay conveyor for transporting tablets, a wetting chamber, a drying chamber and a delivery conveyor. In the wet chamber, the conditions were set so that the tablets were wetted for 60 seconds at 45 ° C., 95% relative humidity. In the drying chamber, the temperature was set at 50 ° C. for 60 seconds. By using this apparatus, brittle tablets were delivered smoothly throughout the process prior to moisture treatment.

c. Sintered

Another method is described in US Pat. No. 6,465,010 to Lagoviyer et al., Which discloses a method of increasing tablet strength by sintering tablet components at high temperature and then re-stocking after the temperature is reduced. Components in the formulation include bulking agents, structuring agents, solvents and binders. Bulking agents in the formulation provide a large volume for the total tablet and the content ranges from about 10% to 95% of the total tablet. Suitable bulking agents include carbohydrates (such as sucrose, mannitol, and sorbitol), calcium carbonate, magnesium carbonate and the like. Suitable structural agents should provide a porous support structure that allows for rapid dissolution of the tablet in the mouth. Rescue agents include agar, gelatin, albumin and chondroitin. Preferred structuring agent was gelatin. The amount of gelatin was in the range of about 1 to 3%. The solvent for dissolving the mixture of bulking agent / structuring agent is selected based on its ability to provide the desired porosity in the beads or granulated product upon drying. The solvent can be selected from water, ethyl alcohol, isopropyl alcohol or mixtures thereof. Preferred solvents are mixtures of ethyl alcohol and water in a ratio of 1: 1 to 1: 100. The binder needs to melt in the sintering step to form bonds between the granules and reshape as the final sintering temperature or heating step is reduced. The binder is a water soluble polymer and a preferred binder is poly (ethylene glycol) (PEG) having a molecular weight of about 1,000 to 1,000,000. PEG melts at about 50-90 ° C. PEG has the advantage that it can act as both binder and capillary attractant. The amount of binder polymer ranges from 0.5% to 25% of the final product.

Summary of the Invention

The present invention relates to pharmaceutical tablets that can be melted rapidly in the oral cavity. Such tablets comprise a plurality of highly plastic granules, which granules comprise a porous plastic material, a water penetration enhancer and a binder. The tablet may be a placebo having no active pharmaceutical ingredient. On the other hand, the tablets more often include drugs.

Porous calcined materials for use in the present invention are characterized and / or selected to exhibit flexible deformation when 500 mg of material is compressed at a pressure of less than about 1,500 pounds in a 0.5 inch diameter die. Porous calcined materials typically comprise from about 1% to about 95% of the tablet weight.

The water penetration enhancer of the invention is selected and characterized by carrying out the following steps: First, 200 mg tablets are formed at 300 pounds in a 0.5 inch diameter die. The tablet is then placed on top of 0.5 ml droplets provided on a flat surface where the droplets do not spread, ie the surface is not wetted. If the enhancer tablet absorbs water and shows complete wetting within 60 seconds, the material is suitable as a water penetration enhancer for use in the present invention, as revealed from the appearance of water on the upper surface. Typically, the water penetration enhancer comprises about 1% to about 95% of the tablet weight.

The binders of the present invention are conventional binders selected to enhance granular adhesion at low pressures used to form tablets and sufficiently adhere to each other such that the particles of the porous plastic material and the water penetration enhancer do not have particle separation. The binder typically comprises about 1% to about 90% of the tablet weight.

In one embodiment of the present invention, the porous plastic material and the water penetration enhancer may be the same material, i.e. both the action of providing a material with suitable porosity and the action of providing a material with suitable water permeation properties are applied to the same material. To the tablets. One example in this regard is fructose.

Tablets of the present invention generally have a total tablet weight in the range of about 5 mg to about 5,000 mg, preferably 50 mg to 500 mg. Tablets of the invention are also characterized in that they melt in less than about 90 seconds, preferably less than about 60 seconds in the mouth. In addition to the components described above, tablets may also include one or more additional ingredients such as surfactants, superdisintegrants, superporous hydrogel particles, blowing agents, lubricants, flavoring agents and / or coloring agents.

The method for producing a rapid melting pharmaceutical tablet of the present invention comprises the steps of combining a porous plastic material and a water penetration enhancer to form a mixture thereof; Treating the mixture with an effective amount of binder to form agglomerated particle masses; Sieving and / or drying the aggregated particles to separate the plurality of highly calcined granules; And compressing the high calcined granules under low pressure to obtain a rapid melting pharmaceutical tablet. This method also preferably involves intimately combining the active pharmaceutical ingredient with the porous plastic material, water penetration enhancer and / or binder prior to mixing with the porous plastic material and water penetration enhancer. The tablet compression pressure used to compress the high calcined granules into tablets is generally less than about 150 MPa, preferably less than about 35 MPa, more preferably less than about 10 MPa. Pharmaceutical tablets with rapid dissolution properties prepared by these methods are also contemplated.

Detailed description of the invention

The three main characteristics required for rapid melting tablets are: (i) high porosity of the tablet for water absorption, (ii) water penetration into the tablet core in seconds, and (iii) mechanical strength of the tablet for ease of handling. Costs high. The three purification properties are achieved simultaneously in accordance with the principles of the present invention by combining chemical components imparting the properties described above. Accordingly, the pharmaceutical tablet of the present invention comprises three kinds of components: (i) porous and calcined material (component 1); (ii) water penetration enhancers (component 2); And (iii) binder (component 3). When these three main components are combined and processed as described herein, high calcined granules can be obtained. High calcined granules can be compressed at low pressure to form quick melt pharmaceutical tablets.

As used herein, “high calcined granules” refers to granules that have been compressed into quick melt tablets in accordance with the principles of the present invention. In particular, such granules are high plasticity when 500 mg granules compressed to a pressure of less than 1,500 pounds in a 0.5-inch diameter die exhibit a tablet hardness of at least 7 Newtons (N) or less than about 5% fracture. Tablets prepared by compressing these high calcined granules at low temperatures exhibit high porosity and exceptionally low degree of fracture. These tablets made of high calcined granules, when placed in the mouth, especially the tongue, melt very quickly.

As used herein, the term "melt" means that the tablet form is damaged in a pasty structure that is susceptible to disintegration or partial dissolution. Melt time depends on the size and dimensions of the quick melt tablet, but in general, the smaller the tablet, the faster the melt. Melt times vary from less than a few seconds for tablets of small dimensions to over 60 seconds for large tablets.

To any one of the three components described above, surfactants, superdisintegrants, superporous hydrogel particles, blowing agents, lubricants, flavoring agents or coloring agents may be added to improve purification performance and / or manufacturing process. Alternatively, one of the other components may be added to the tablet formulation after formation of the high calcined granules and before being compressed into tablets.

Figure 1 shows a typical method for producing high calcined granules and quick melt tablets according to the present invention. In the process shown in FIG. 1, the drug is mixed with component 1 and component 2 before granulation. However, as discussed in detail later, the drug does not need to be mixed with components 1 and 2 before it is granulated. Component 1 and Component 2 may also be the same chemical compound.

In another embodiment, as shown in FIG. 2, the drug is added to component 3. This procedure is useful for drugs with very low dosages or already in solution.

As another embodiment of the present invention, as shown in FIG. 3, high calcined granules without drug can be prepared first and the drugs can be mixed later. This procedure is particularly useful when the drug is sensitive to the solvent used for granulation.

Alternatively, as shown in FIG. 4, components 1 and 2 need not be granulated at the same time. Component 1 is granulated independently of component 2 to form two different types of aggregated particles (granules). The granules of component 1 and the granules of component 2 can be mixed with the other components. Granules comprising component 1 and component 2 may also be granulated with component 3. At least one drug may be added at any stage prior to the low compression stage.

As is evident from the foregoing, it is possible to produce rapid melting tablets with similar properties by numerous modifications in the process steps.

Basis of Three-Component System

Component 1 of the present invention is selected from pharmaceutically acceptable porous and plastic excipients. Porous calcined materials are sometimes water soluble or water dispersible upon contact with water. Suitable powders having a porous structure and plastic properties show that the tablets formed retain their shape and size, i.e., plastic properties, when 500 mg of this powder is pressurized at pressures less than 1,500 pounds using a 0.5-inch diameter die. Powder that can be prepared to Plastic deformation of the powder significantly increases the probability of internal particle contact required to form bonds between particles.

If the porous and calcined material of the present invention is a polymer, it is essential to prevent the formation of a viscous layer of material on the tablet surface when dissolved in an aqueous medium. One method of making such tablets is to mix the porous and calcined material (component 1) with a water penetration enhancer (component 2) in a certain proportion and compress them at low pressure resulting in plastic deformation of the porous and calcined material, resulting in intimate contact between the particles. How to create it. In this process, the porous and calcined particles are separated by water penetrating particles (component 2) and prevent the formation of a viscous layer on the tablet surface. In the present invention, component 1 and component 2 are different materials, but in some cases they may be the same material.

Porous and plastic materials may be in intimate contact to increase the probability of bonding by compression, but the formation of very strong bonds between granules at the pressures described above requires a suitable binder (component 3). The binder here can be immobilized during granulation of the porous material and the water penetration enhancer. Without the binder, the two components are likely to separate during mixing. The binder may be a liquid or semisolid, for example a binder in paste form. If the binder is in a liquid or semisolid state, it should not significantly disrupt the porous structure of the porous material. One way to achieve this is to use a high concentration of binder to lower the water activity. Another way to achieve this is to allow only a short contact time with a porous structure that is not destroyed by the binder solution when producing granules using a relatively low concentration of binder. For example, the solvent is dried immediately after wetting in a fluidized bed granulator so that the porous structure can be maintained even when a relatively low concentration of binder is used.

Components of Rapid Melt Tablets Based on High Calcined Granules

Component 1: Porous and Plastic Material

As used herein, the term “porous plastic material” and its equivalents include (i) about 0.14 or more porosity (defined by pore volume divided by total volume) or density less than about 0.86 (weight divided by volume). Plastic deformation (i.e., the tablets formed retain their shape and size) when compressing 500 mg of the powder at a pressure of less than 1,500 pounds using a porous material with a porous material and (ii) a 0.5-inch diameter die Refers to the substance being. In general, when the compressive force exceeds 1,500 pounds, the tablets formed often do not maintain rapid melting properties.

Porous and calcined materials are preferably water soluble materials. Porous and calcined materials with high water solubility may occupy 1% to 95% of the total tablet weight. If the concentration of component 1 is less than about 1%, it may not provide sufficient contact with other components, increasing the chance of binding by compression. If the concentration of component 1 is higher than about 95%, other components such as component 2, component 3, drugs, lubricants, etc. may not be included.

The porous and calcined materials of the present invention may be commercially available or may be prepared by various methods such as spray drying, granulation with a fluid bed granulator, and the like. Porous and calcined materials that can be used to prepare high calcined granules include maltodextrin, dextrin, ethylcellulose as well as sugars, including fructose, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, erythritol and xylitol Organic polymers such as, but not limited to, polymethacrylate and pregelatinized starch (such as LYCATAB ^® C, manufactured by Roquette American Inc.). Maltodextrins are commercially available, such as the MALTRIN series (maltodextrin and corn syrup solids are formed by Grain Processing Corp.) and the MALTRIN QD series (maltodextrin and corn test solids rapid dispersion by Grain Processing Corp.) Formed) and GLUCIDEX ^® IT (maltodextrin and spray dried glucose syrup manufactured by Roquette American Inc.). Maltrin QD series and ADVANTOSE 95 Fructose or combinations thereof are preferred because they are prepared to have high porosity in aggregates in addition to excellent binding properties.

Other materials capable of forming suitable porous and plastic structures include gum arabic, xanthan gum and derivatives thereof, guar gum and derivatives thereof, seaweed gum, carrageenan, dextran, gelatin, alginate, pectin, starch and starch derivatives (e.g. Homopolymers or copolymers of hydroxypropyl starch or carboxymethyl starch, cellulose esters (such as carboxymethylcellulose or cellulose ether hydroxyethyl-methylcellulose), unsaturated acids (such as acrylic acid or salts thereof), unsaturated amides such as acrylamide Homopolymers or copolymers of), homopolymers or copolymers of ethylene imine, vinyl polymers (such as poly (vinyl alcohol)), vinyl esters (such as vinylpyrrolidone, vinyloxazolidone, vinylmethyloxazolidone, vinylamine , And homopolymers or copolymers of vinylpyridine), alkylglycols and polyal Kylene oxide (such as polyethylene oxide) and oxyethylene alkyl ether, dexrate, dextrin, dextrose, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, calcium sulfate, calcium carbonate, dibasic phosphoric acid Calcium, tribasic calcium phosphate and carboxymethylcellulose-calcium salts.

Component 2: water penetration enhancer

The water penetration enhancer of the present invention is used to speed up tablet disintegration. As used herein, a "water penetration enhancer" is defined phenomena as follows: When 200 mg of penetration enhancement candidate is compressed to 300 pounds in a 0.5-inch diameter die, the tablets formed are not wetted. When placed on top of a 0.5 ml droplet placed on a flat surface, ie when the droplet does not spread on the surface, it must be fully wetted within 60 seconds. Complete wetting is evidenced by the appearance of water on top of the tablet within the 60 second time interval.

In order to be used in the manufacture of rapid melting tablets, the water penetration enhancer must be highly water soluble or at least highly dispersible. The water penetration enhancer may occupy 10% to 95% of the total tablet weight. Typically, when the concentration of component 2 is less than about 10%, it is not possible to effectively provide a water penetration enhancement effect. If the concentration of component 2 is higher than about 95%, other components such as component 1, component 3, drugs, lubricants and the like may not be included.

Common water penetration enhancers are highly water soluble carbohydrates commonly used as diluents. Any type of carbohydrate can be used in the formulations described herein. Examples are dextrates, dextrins, dextrose, fructose, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, erythritol and xylitol. Less water soluble but highly dispersible diluents are microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, calcium sulfate, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate and carboxymethylcellulose-calcium salt to be. Various combinations of carbohydrates and polymers can also be used. Examples are STARLAC ^® (15% corn starch and 85% alpha-lactose be a spray-dried solid component containing whiskers, Roquette American, Inc. Manufacturing), MICROCELAC ^® (75% alpha-lactose days beard and microcrystalline property 25% a lactose days beard and spray dried compounds, technology & Meggle excipients prepared consisting of 25% cellulose powder) the spray dried cellulose-containing solid component, Meggle excipients & technology Ltd.) and CELLACTOSE ^® (75% alpha. Preferred grades of materials used as water penetration enhancers or bulk diluents are direct compression grades. More preferred are materials prepared to have high porosity by spray drying. Examples of porous water penetration enhancers or bulk diluents are STARLAC ^® , MICROCELAC ^® , CELLACTOSE ^® , MANNOGEM EZ Spray ^® (spray dried mannitol, manufactured by SPI Pharma. Inc.).

Component 3: Binder

In the present invention, the main action of the binder is to make a bond between component 1 and component 2 so that the two components do not separate and increase the binding efficiency between the granules at the low compression pressure used to prepare the tablet. These binders may be in liquid or semisolid form, depending on the granulation method. One requirement for the binder is that the binder in solution or semisolid form should not significantly destroy the porous structure of the material by dissolution. Therefore, it is important to maintain the porous structure of components 1 and 2 as much as possible. This can be achieved, for example, by simply lowering the water activity using a high concentration of binder. To check the suitability of the binder, a simple test can be performed: 1 mL of binder is added to 0.5 g of porous and calcined material; If the porous material does not dissolve entirely within 10 seconds, the binder is a possible candidate that can be used to prepare a quick melt tablet in accordance with the principles of the present invention.

After the wet granules are dried, the solidified binder preferably dissolves immediately upon contact with water. The type and amount of binder in solution for wet granulation can be adjusted so that the granules have desired physical properties such as high plasticity and good binding properties. Other pharmaceutically acceptable organic solvents, such as ethanol, can be used as the solvent for the binder, which can further reduce the dissolution of the porous material. Other substances include carbohydrate and acacia, alginic acid, CARBOMER, carboxymethyl cellulose, cellulose, dextrin, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polydextrose as listed in component 2. Polymers such as os, poly (ethylene oxide), povidone and sodium alginate.

Other ingredients

In addition to the three components described above, several other components may also be added to the tablet formulation to improve tablet quality and performance. Disintegrants, sweeteners, flavors, colorings, sours and lubricants may be added. Examples of disintegrants include starch, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate and ultraporous hydrogels. Sweeteners include natural and artificial sweeteners such as sodium saccharin, aspartame and cyclamate. Examples of flavoring agents include fruit flavors, bubble gum flavors, and the like. Colorants include food dyes, food lake dyes, and the like. Sour taste agents that cause saliva in use include citric acid. Lubricants include sodium stearate, stearic acid, poly (ethylene glycol), polyoxypropylene-polyoxyethylene block polymers, talc, sodium stearyl fumarate, colloidal silicon dioxide, and the like.

Method for preparing rapid melting tablet based on high calcined granules

Addition of Active Ingredients : An active pharmaceutical ingredient, such as a drug, can be added to the formulation by several methods. The drug or drugs are mixed with component 1 and component 2 and then wet granulated as shown in FIG. 1. The drug or drugs may also be added to component 3 for granulation as shown in FIG. 2. Alternatively, the drug or drugs may be mixed with high calcined placebo granules as shown in FIG. 3. High calcined placebo granules are prepared in the absence of drugs or drugs. Another point of introducing a drug into the formulation, which may vary depending on the stability characteristics of the drug, is well understood by those skilled in the art. Herein, "dietary supplement" is considered to be within the definition of "active pharmaceutical ingredient."

The active pharmaceutical ingredient can be in crystalline, amorphous or any solid form. Drug particles can be coated to mask taste or to control drug release properties. Surfactants, superdisintegrants, ultraporous hydrogel particles, blowing agents, lubricants, flavoring agents or colorants may optionally be added to improve tablet performance and / or manufacturing processes.

Granulation for producing high calcined granules : Depending on the granulation state, the granulation method can be changed. In wet granulation, other desired materials other than drug, component 1, component 2, and other essential ingredients may be added. After mixing all the components, the solution for wet granulation is slowly added, while the dry material is continuously stirred until the wet mass obtains the desired properties. Low shear granulators, high shear granulators or fluidized bed granulators are preferred for wet granulation to avoid excessive damage to the internal porous structure of the primary particles. In the granulation process, the high calcined granules of component 1 and component 2 are made separately and then mixed later. During the wet granulation process, the particles adhere to each other and a liquid bridge is formed between the particles. For this reason, the wet granulation method is called a densification process. The resulting wet mass is screened and dried through a sieve having the desired sieve size.

The component material is chosen such that the granules obtained are highly calcined even after drying. High calcined granules can be used to make tablets by compression. The exact steps for wet granulation may vary depending on the device used for wet granulation. An important point here is to produce high calcined granules.

During wet granulation, the dry component is partially dissolved in the solution, which may result in some loss of porosity of the primary particles. To minimize this, wet granulation solutions with high concentration binders are used to reduce the solubility of solutions for diluents and dry binders. Another advantage of using wet granulation solutions of high concentration binders is that the amount of binder deposited on the particles is so great that it leads to a marked improvement in interparticle bonding during compaction. The term "high concentration binder" refers to a concentration higher than the concentration used for conventional granulation, preferably close to the concentration of the saturated solution of the binder. The granulating binder is not limited to the solution state, and semisolids may also be added as the binder in the granulation.

Sieving and Drying : In the sieving step, the wet mass passes through a sieve before drying. Drying methods or conditions may vary to achieve high plasticity properties of the final dry granules. Wet granulation, sieving and drying steps may be combined depending on the granulation device.

Pre-compression : The granules can be mixed with superdisintegrants, superporous hydrogel particles, blowing agents, lubricants, flavors or colorants in the blender before being compressed at low pressure (1-150 MPa).

Compression : In order for the tablet to melt quickly in the mouth, the tablet must quickly absorb water into its inner core. Therefore, it is important to maintain high porosity in compressed tablets. Usually, low pressure is applied to maintain high porosity after compression. However, if tablets are made at low compression pressure, they exhibit poor degree of fracture and hardness. An important difference between tablets made according to the invention and other so-called "quickly soluble tablets" is that the tablets of the invention have high plasticity. When a force or stress is applied to the granules, the stress is released in two different ways. When the granules return to their original shape or form, they are called elastic deformation. If the granules do not fully recover to their shape after the stress is released, they are called plastic deformation. Both elastic and plastic deformation can occur at the same time, but only one effect prevails during the compression process [Dor, P. et al . , Pharma. Devel. & Tech. , 5: 575-577, 2000]. As the force applied increases, the thickness of the tablet decreases. On the other hand, when compacting granules, the granules undergo particle rearrangement, elastic deformation, plastic deformation and bridging. Purification gains significant strength only in the plastic deformation and crushing steps. In this method, the force required to reach the plastic deformation step is significantly reduced by using high calcined granules. Since this step comes quickly, significant tablet strength can be obtained while significant porosity can be maintained. Due to the high plasticity of the granules it is possible to achieve very low levels of crushing at the initial stage of compression (ie in the low pressure region) when the porosity between the particles is not significantly reduced. Combining the porosity and internal porosity of the plastic material and the water penetration enhancer, the tablet can maintain very high porosity. High strength and low degree of breakdown can be achieved at low compression pressures.

In short, quick melt tablets can be prepared at low compression pressures using high calcined granules comprising the three components used for granulation. High binder concentrations are important for depositing large amounts of binder on the surface of the particles. Conventional wet granulation methods based on a three component system can be used to make ideal high calcined granules for producing rapid melt tablets at low compression pressures.

Active pharmaceutical ingredients

The present invention can utilize a wide range of active pharmaceutical ingredients, it is various enough to not be mentioned in the present specification. Representative classes of drugs that may be formulated into, for example, the rapid melting tablets of the present invention include:

Antimigraine drugs such as almotriptan, ergotamine tartrate, probatriptan, methiserzide maleate, sumatriptan succinate, zolmitriptan and the like;

Antirheumatic drugs such as auranopine, azathioprine, cyclosporin, hydroxychloroquine sulfate, refunoamide, methotrexate, penicillamine, sulfasalazine, and the like;

Acetaminophen, Aspirin, Dichlorophenac, Etodolak, Phenopropene, Ibuprofen, Ketoprofen, Naproxen, Indolmethacin, Ketorolac, Sulindac, Tolmetin, Meclopannamate, Mefennamic acid, Nabumethone, Non-steroidal anti-inflammatory drugs, such as meloxycam, pyroxicam, celecoxib, lofecoxib, and the like;

Opioids such as buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, lavorfanol, meperidine, morphine, oxycodone, pentazosin, propoxyphene, tramadol and the like;

Anti-mycobacterium drugs such as aminosalicylic acid salts, clofazimine, cycloserine, ethionamide, rifabutin and the like;

Antiparasitic drugs such as albendazole, ivermesin, mebendazole, prazicuantel and the like;

Antiviral drugs such as valacyclovir, didanosine, famcyclovir, valgancyclovir, indinavir, lamivudine, nelpinavir mesylate, nevirapine, ritonavir, stavudine, oseltamivir phosphate, and the like;

Beta-lactams such as amoxicillin, amoxicillin and potassium clavulanate, ampicillin, cefuroxime sodium, cefuroxime acetyl, penicillin G and Y salts, ceftitorene, cepisimine, xaxacillin sodium, dicloxacillin sodium and the like;

Macrolide antibiotics such as erythromycin estoleate, erythromycin ethyl succinate, erythromycin stearate and the like;

Fluoroquinolones such as ciprofloxacin, enoxacin and the like;

Tetracyclines such as demeclocycline hydrochloride, doxycycline calcium, tetracycline, tetracycline hydrochloride and the like;

Alkylating agents such as altretamine, busulfan, chlorambucil, melphalan, cyclophosphamide, procarbazine hydrochloride, temozolomide and the like;

Anti-metabolites such as methotrexate, mercaptopurine, thioguanine, and the like;

Hormonal drugs and antagonists such as bicalutamide, flutamide, nirutamide, aminoglutetimide, anastrozole, exemestane, letrozole, tamoxifen citrate, toremifene citrate and the like;

Mitosis inhibitors such as etoposide phosphate and the like;

Immunosuppressants such as azathioprine, cyclosporin, mycophenolate mofetil, sirolimus, tacrolimus and the like;

Amiodarone hydrochloride, digoxin, disopyramid phosphate, dofetilide, flkanide acetate, mesyretine hydrochloride, moricisine hydrochloride, procainamide hydrochloride, propaphenone hydrochloride, quinidine sulfate, quinidine glucoside Arrhythmia drugs such as nate, sotalol hydrochloride, tocainide and the like;

Doxazosin mesylate, prazosin hydrochloride, terrazosin hydrochloride, benazepril, captopril, clonidine hydrochloride, enalapril, hydrorazine hydrochloride, labetalol hydrochloride, losartan potassium, methyldopate hydrochloride, Antioxidants such as minoxidil, moexipril, trandolapril, candesartan, irbesartan, losartan, telmisartan, valsartan, guanabenz acetate, guanadrel sulfate, guanfacin hydrochloride, reserpin, etc. Hypertension drugs;

Beta- such as acebutolol, atenool, betasolol, bisoprool, carteol, carvedilol, labetaol, metoprolol, nadolol, phenbutolol, pindolol, propranolol, soltalol, timolol and the like Adrenaline blocking drugs;

Calcium-channel blockers such as amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, verapamil, and the like;

Hypolipidemic drugs such as fenofibrate, gemfibrozil, niacin, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, and the like;

Nitrates such as isosorbide dinitrate, nitroglycerin, nitroprusside sodium and the like;

Carbamazepine, clonazepam, ethoxushimid, felbamate, gabapentin, lamotrigine, levetiracetam, oxacarbazepine, phenobarbital, phenytoin, primidone, tiagabine, topiramate, valproic acid, divalpro Anticonvulsants, such as x sodium, zonamide, and the like;

Mirtazapine, bupropion, amoxapine, phenelzin, tranilcipromin, citalopram, fluoretine, fluvosamine, parosetin, sertraline, venlafaxine, maprotyrin, trazodone, nefazodone, amitrip Antidepressants such as tilin, clomipramine, desipramine, decepine, imipramine, nortriptyline, protropyline, trimipramine and the like;

Antipsychotic drugs such as chlorpromazine, thiolidazine, roxapin, mollindon, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, flufenazine, haloperidol, perphenazine, trifluoroperazine, thiocytene, etc. ;

Alprazolam, Lorazepam, Oxazepam, Chlordiazepoxide, Chlorazate, Diazepam, Halasepam, Midazolam, Triazolam, Zaleplon, Zolpidem, Estazollam, Temezepam, Flurazzepam, Cuasepam Anti-anxiety agents, sedatives and sleeping pills, such as meprobamate, phenobarbital, chloral hydrate, ethchlorbinol, glutetimide, pentobarbital, secobarbital and the like;

Degenerative neurodegenerative drugs such as amantadine, benztropin mesylate, carbidopa and levodopa, donepezil, bromocriptine, pergolide, pramipesol, rofinilol and the like;

Eye drops for glaucoma, such as acetazolamide, dichlorphenamide, metazolamide, and the like;

Acid-pepsin therapeutic drugs such as aluminum carbonate, aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, calcium carbonate, magaldrate and the like;

Bismuth salts, cimetidine, pamotidine, nizatidine, ranitidine, misoprostol, lansoprazole, omeprazole, pantoprazole, rabeprazole, sucralate and the like;

Buclizin, Cyclizin, Dimenhydrinate, Diphenhydramine, Meclizin, Dronabinol, Chlorpromazine, Perphenazine, Prochlorperazine, Promethazine, Thiethylperazine, Tripleluproazine Antiseptics, such as dolacetrone, granistron, ondansetron, dexamethasone, larasephamm and the like;

Gastrointestinal motility drugs such as bisacodeyl, diphenoxylate hydrochloride and atropine sulphate, docusate salts, loperamide, magnesium salts, metoclopramide, usodiol and the like;

Coagulants and anticoagulants such as clopidogrel bisulfate, phytonadione, ticlopidine, warfarin sodium and the like;

Hematopoietic drugs, such as iron salts;

Adrenaline hormones such as cortisone, hydrocortisone, methylprednisolone, prednisone, triamicinolone, betamethasone, dexamethasone, fludrocortisone, and the like;

Antidiabetics, such as acarbose, metformin, nateglinide, repaglinide, acetohexamide, chlorpropamide, tolazamide, tolbutamide, glymeprid, glipidide, gluburide, pioglitazone, rosiglitazone, etc. drug;

Contraceptives such as noretin drone, norgestrel, levonorgestrel and the like;

Female sex hormones such as estradiol and its esters, estrogens, estropiates, methoxyprogesterone, mifepristone, noretin drone acetate, progesterone, raloxyphene and the like;

Thyroid and antithyroid drugs such as iodide, levothyroxine sodium, lyothyronine sodium, lyotrix, methiazole, propylthiouracil and the like;

Amylolide hydrochloride, bumetanide, ethacrynic acid, furosemide, torsemide, hydrochlorothiazide, chlorthiazide, chlorthalidone, indafamid, metorazone, polythiazide, quintazone, Diuretics such as tricometiazide, spironolactone, triamterene and the like;

Electrolytic materials such as chelated magnesium, magnesium chloride, magnesium hydroxide, magnesium oxide, potassium salt and the like;

Gout treatment drugs such as allopurinol, colchicine, probenside, sulfinpyrazone, and the like;

Asthma treatments such as albuterol sulfate, montelukast sodium, theophylline, zileuton and the like;

Acrivastin, Azatadine, Bromopheniramine Maleate, Carbinoxamine Maleate, Cetirizine Hydrochloride, Chlorfeniramine Maleate, Diphenhydramine Hydrochloride, Clemastine Fumarate, Ciprohepadin Hydrochloride, Fexofenadine Antihistamines such as hydroxyzine, loratadine, desloratadine and the like;

Cough and cold drugs such as dextromethorphan hydrobromide, guipensine, pseudoephedrine hydrochloride, and the like; And

Nutritional supplements.

Characterization of Rapid Melt Tablets

Strength Tablets: Tablets strength was measured by a texture analyzer ^{(TA XT2 ®, Texture Technologies Corp} .; Scarsdale, NY). Diameter damage (ie, apparent breakage) of the tablet was considered a label of tablet strength.

Disintegration test : This method is a modification of the method developed by Dor et al. (Described above). This method used a tissue analyzer (TA XT2 ^® ). Tablets were attached to the bottom of the probe attached to the dropping cell by a very thin adhesive layer or double-sided copper tape. The tablet was approached with constant force on a filter paper immersed in water connected to a water reservoir. As the tablets began to disintegrate, the speed at which the probe moved showed a sudden increase. This rate of increase continued until the tablets disintegrated. The time at which the increased travel speed ceased was considered the disintegration time.

In vivo disintegration testing of FDT was performed on volunteers. Volunteers were randomly selected, tested and instructed to flush their mouth with water. The tablets were placed on the volunteers' tongues and immediately operated by a stopwatch to measure disintegration time. Volunteers were allowed to use their tongues to move the FDT to the ceiling of the mouth, to smoothly roll the tablet without biting, or to roll from side to side. As soon as the last identifiable tablet disintegrated, the stopwatch was stopped and the time was recorded.

Breakability Test : The tablet breakage test was performed according to the USP25 tablet breakage method described in the Table Friability of the General chapters describing general tests and analysis.

1 is a schematic of general process steps for producing high calcined granules and rapid melting tablets.

FIG. 2 shows a process method in which drug is added to component 3 (as described in Example 1) to produce high calcined granules and quick melt tablets.

3 shows a process method in which a drug is added to high calcined granules (as described in Example 14) to produce high calcined granules and quick melt tablets.

4 illustrates another tablet forming process in which component 1 and component 2 are granulated separately and then later combined to form high calcined granules. The granules of component 1 and component 2 can also be further granulated with the aid of component 3. The drug may be added at any stage prior to the low pressure compression step.

The present invention is described by way of example, but not by way of limitation, for illustrative purposes.

Example 1 :

ingredient

Maltrin QD580 6g

Mannogem EZ Spray 24g

Maltrin (component 1) is Grain Processing Corp. Fast-dispersed maltodextrin and corn syrup solids marketed by (Muscatine, IA) and Mannogem EZ Spray (Component 2) were manufactured by SPI Pharma.Inc. Spray-dried mannitol sold by New Castle, DE. Maltrin QD580 with 20-60 sieve size was used. Maltrin QD580 and Mannogem EZ Spray were mixed together. The mass mixture was then geometrically mixed with the small mixture to give a complete mixture. 7 ml of 70% sucrose binding solution (component 3) was added while mixing this mixture with a mixer. This mixture was passed through No. 18 sieve and air dried at room temperature. The dry mixture was passed through a No. 30 sieve. The granules were then compressed into tablets by 300 pounds in a 1/2 inch die by a Kaver compressor. The weight of each tablet was 500 mg. The hardness of the tablet was 65.2 N and the disintegration time was 23 seconds.

Example 2

ingredient:

Maltrin 180 6g

Mannogem EZ Spray 24g                 

Maltrin 180 and Mannogem EZ spray were mixed together. The mass mixture was then geometrically mixed with the small mixture to give a complete mixture. 6 ml of 70% sucrose binding solution was added while mixing this mixture with a mixer. This mixture was passed through No. 18 sieve and air dried at room temperature. The dry mixture was passed through a No. 30 sieve. The granules were then compressed into tablets by 300 pounds in a 1/2 inch die by a Kaver compressor. The weight of each tablet was 500 mg. The hardness of the tablet was 7.3 N. Maltrin 180 has the exact same molecular structure as Maltrin QD580. Only one difference is the bulk density. Maltrin 180 is non-porous with a dense bulk density of 0.61 g / cc, and Matrin QD580 is porous with a dense bulk density of 0.40 g / cc. Since Maltrin 180 is nonporous, it will be much less plastically deformed when Maltrin 180 is compressed compared to Maltrin QD580 compressed under the same conditions. When compressing the granules at low pressure, higher plastic deformation will result in higher bond formation between granules. The main difference between Examples 1 and 2 is the use of Maltrin 180 in Example 2 instead of the Maltrin QD580 in Example 1. Tablet strength was significantly increased when using Maltrin QD580.

Example 3

Maltrin QD580 with Nos. 20-60 sieve size was used and Mannogem EZ spray passed through No. 50 sieve. The two materials were mixed in the proportions shown in the table below. The granules were compressed into tablets by 300 pounds on a 1/2 inch die by means of a caber compressor. The weight of each tablet was 500 mg. The hardness of the tablets prepared is shown in Table 1 below. Directly compressing the two materials without granulating by adding a binder could not yield a tablet with the desired strength compared to the tablet in Example 1. Tablets made with pure Maltrin QD580 had a higher strength than tablets made with pure Mannogem EZ spray due to the higher plastic deformation caused by Maltrin QD580 during the compression process.

Example 4

Maltrin QD580 with 20-60 sieve size was used. Mannogem EZ spray particles passed through No. 50 sieve. 100 g Maltrin QD580 and 400 g Mannogem EZ spray were mixed. This mixture was placed in a Kitchen-Aid mixer. The speed was kept at 1 when dry mixing. Dry mixing took 5 minutes. 100 ml of sucrose solution ranging from 10% to 70% sucrose solution was pumped into the mixer at a rate of 40 ml / min by Gilson mini Puls2 peristaltic pump. After introducing all the binder solution, the mixer was run for another 2 minutes. The wet mass was passed through No. 8 sieve. The granules were compressed into tablets by 300 pounds in a 1/2 inch die by means of a Kaver compressor. The weight of each tablet was 500 mg. The results are shown in Table 2 below.

The results indicate that as the concentration of the sucrose solution increases, the hardness increases substantially as more plastic strains induce binding better. This seems to be because the porous structure is preserved by using a binder solution having a high sucrose concentration.

Example 5

ingredient:                 

Maltrin QD500 6g

StarLac 12g

Mannogem EZ Spray 12g

StarLac (Component 1) is manufactured by Roquette American, Inc. Spray-dried solids containing 15% cornstarch and 85% alpha-lactose monohydrate sold by Keokuk, IA. To the mixture of the three components was slowly added 6 ml (component 3) of 70% sorbitol solution. The wet mass obtained was passed through a No. 18 sieve and the wet granules were left in a 50 ° C. oven for 22 hours. The granules were removed from the oven and left for 2 hours in air at room temperature and passed through a No. 30 sieve. 200 mg of granules were placed in a 0.375 inch die and then compressed at 150 pounds. The formed tablets melted in less than 10 seconds, usually within 6 seconds. The fracture test was conducted according to the US Pharmacopeia and the fracture degree was 1.3%.

Example 6

ingredient:

Maltrin QD580 6g

StarLac 12g

Mannogem EZ Spray 12g

The method is the same as described in Example 5. 200 mg tablets were obtained. Disintegration time for these tablets was determined to be 8 seconds.

Example 7

ingredient:

Maltrin QD580 6g

StarLac 12g

12 g of silicified microcrystalline cellulose

Loratadine 1.8g

The silicified microcrystalline cellulose (component 2) used is PROSOLV SMCC 90, sold by Fenwest Company (Patterson, NY). To the mixture of the four components 6 ml of 70% sorbitol solution, preferably 0.2 ml aliquot of sorbitol solution was added slowly while mixing with a hand mixer. The obtained wet mass was passed through No. 18 sieve and the wet granules were placed in a 50 ° C. oven for 22 hours. The granules were removed from the oven and left for 2 hours in air at room temperature and passed through a No. 30 sieve. The granules were placed in a 0.375 inch die and then compacted at 150 pounds. Each tablet weighed 200 mg. The average disintegration time was 13 seconds.

Example 8

ingredient:

Maltrin QD580 6g

Mannogem EZ Spray 24g

Aspirin 17.8 g

Zinc Gluconate 0.98g

Glucosamine Sulfate 4.95g                 

Maltrin QD580 with 20-60 sieve size was used. Maltrin QD580, Mannogem, Aspirin, Zinc Gluconate and Glucosamine Sulfate were mixed together. While mixing with a hand mixer, 8 ml of 70% sucrose binder solution was added to the mixture. This mixture was passed through No. 18 sieve and air dried at room temperature. The dried mixture was passed through No. 30 sieve. To each 100 g of granules was added 3 g of POLYPLASDONE ^® XL (International Specialty Products Corporation, Crospovidone manufactured by Calvert Cit, KY) and 1.7 g of aspartame. The resulting mixture was compressed into tablets by 300 pounds on a 7/16 inch die by a Kaver compressor. Each tablet weighed 314 mg. The average disintegration time was 14.3 seconds and the degree of breakage was 0.45%. The hardness of the tablet was 54.9N.

Example 9

ingredient:

Maltrin QD580 200g

Mannogem EZ Spray 767 g

Loratadine 33g

Maltrin QD580 was sieved through No. 30 sieve and Mannogem EZ spray was sifted through No. 50 sieve. The mixture of the three components was poured into a 6 liter high shear mixer vessel. For mixing the Diasona mixer granulator P1-6 was used at an impeller speed of 200 rpm and a chopper speed of 1,500 rpm. All components were premixed for 1 minute and then 160 ml of 50% sucrose dissolved in 50% ethanol solution was pumped at a rate of 400 ml / min. The wet mass was mixed for 2 more minutes. After stopping the binding solution, the wet mass was sieved through No. 8 sieve and air dried. The dried granules were sieved through No. 16 sieve. Per 100 g granules, 3 g POLYPLASDONE® XL was added and mixed. The resulting mixture was compressed into tablets by 300 pounds on a 7/16 inch die by a Kaver compressor. Each tablet weighed 309 mg with an average disintegration time of 9 seconds and a tablet hardness of 20.6 N.

Example 10

ingredient:

Maltrin QD580 89.4g

Mannogem EZ Spray 357.6 g

Folic acid 33.0g

0.5 g of vitamin B12

Maltrin QD580 was sieved through No. 30 sieve and Mannogem EZ spray was sifted through No. 50 sieve. The four components were mixed and the mixture was poured into a 6 liter high shear mixer vessel. Diasona mixer granulator P1-6 was used for mixing at an impeller speed of 200 rpm and a chopper speed of 1500 rpm. All components were premixed for 1 minute. 100 ml of 50% sucrose dissolved in 50% ethanol solution was pumped at a rate of 200 ml / min. The wet mass was mixed for 2 more minutes. After stopping the binding solution, the wet mass was sieved through No. 8 sieve and air dried. The dried granules were sieved through No. 16 sieve. Per 100 g granules, 3 g POLYPLASDONE® XL was added and mixed. The resulting mixture was compressed into tablets by 200 pounds in a 3/8 inch die by a Kaver compressor. Each tablet weighed 309 mg. The average disintegration time was 6 seconds. The hardness of the tablet was 18.4 N.

Example 11

ingredient:

Maltrin QD580 6g

Mannogem EZ Spray 24g

Acetaminophen 30g

Maltrin QD580 with 20-60 sieve size was used. Maltrin QD580, Mannogem, Acetaminophen were mixed together. While mixing with a hand mixer, 8 ml of 70% sucrose binding solution was added to the mixture. The mixture was passed through No. 18 sieve and air dried indoors. The dried mixture was sieved through No. 30 sieve. To each 100 g of granules 3 g of POLYPLASDONE ^® XL was added and mixed. The resulting mixture was compressed into tablets by 300 pounds on a 9/16 inch die by a Kaver compressor. Each tablet weighed 309 mg. The average disintegration time was 25 seconds and the tablet hardness was 49.2N.

Example 12

ingredient:                 

Maltrin QD580 5g

25g calcium carbonate

Maltrin QD580 with 20-60 sieve size was used. Maltrin QD580 and calcium carbonate (component 2) were mixed. While mixing with a hand mixer, 6 ml of 70% sucrose binding solution was added to the mixture. The mixture was passed through No. 18 sieve and air dried indoors. The dried mixture was sieved through No. 30 sieve. The resulting mixture was compressed into tablets by 500 pounds on a 9/16 inch die by a Kaver compressor. The weight of each tablet was 1000 mg. The average disintegration time was 25 seconds and the tablet hardness was 24.5 N.

Example 13

ingredient:

Maltrin QD580 6g

Mannogem EZ Spray 24g

3.5 ml of herbal extracts (aqueous solution)

Maltrin QD580 passed through No. 30 sieve, and Mannogem EZ Spray passed through No. 50 sieve. Aqueous (2.5 ml) herbal extracts were added to the sucrose solution to create a final sucrose concentration of 70%. While mixing with a hand mixer, 8 ml of 70% sucrose binding solution containing herbal extracts was added to the mixture. The mixture was passed through No. 18 sieve and air dried indoors. The dried mixture was sieved through No. 20 sieve. To each 100 g of granules 3 g of POLYPLASDONE ^® XL was added and mixed. The resulting mixture was compressed into tablets by 250 pounds on a 5/16 inch die by a Kaver compressor. Each tablet weighed 150 mg. The average disintegration time was 7 seconds and the tablet hardness was 25 N.

Example 14

ingredient:

Maltrin QD580 6g

Mannogem EZ Spray 24g

Maltrin QD580 passed through No. 30 sieve, and Mannogem EZ Spray passed through No. 50 sieve. While mixing with a hand mixer, 8 ml of 85% sucrose binding solution was added to the mixture. The mixture was passed through No. 18 sieve and air dried indoors. The dried mixture was sieved through No. 18 sieve. Sodium bicarbonate was mixed to the high calcined granules in a 2: 1 ratio (high calcined granules: sodium bicarbonate) with 2% lubricant. The final mixture was compressed into tablets by 200 pounds in a 1/4 inch die by means of a caber compressor. Each tablet weighed 60 mg. The average disintegration time was 7 seconds.

Example 15

ingredient:

Maltrin QD580 200g                 

Mannogem EZ Spray 800g

Maltrin QD580 passed through No. 30 sieve, and Mannogem EZ Spray passed through No. 50 sieve. The mixture of the two components was poured into a 6 liter high shear mixer vessel. Diasona mixer granulator P1-6 was used for mixing at an impeller speed of 200 rpm and a chopper speed of 1500 rpm. All components were premixed for 1 minute and then 240 ml of 50% sucrose dissolved in 50% ethanol solution was pumped at a rate of 400 ml / min. The wet mass was mixed for 2 more minutes. After stopping the binding solution, the wet mass was sieved through No. 8 sieve and air dried. The dried granules were sieved through No. 16 sieve. 2 g of mint oil and 98 g of placebo granules were mixed together. The resulting mixture was compressed into tablets by 250 pounds on a 7/16 inch die by a Kaver compressor. The weight of each tablet was 300 mg. The average disintegration time was 6.6 seconds and the hardness of the tablet was 16.5 N.

Example 16

ingredient:

Advantose FS 95 Fructose (SPI Pharma) 31.21 g

Mannogem EZ Spray 93.63 g

Advantose FS 95 fructose is an air dry substance of 95% fructose and 5% starch. Advantose FS 95 fructose and Mannogem EZ spray were mixed together and 25.2 g of a 50% sucrose solution was added to the mixture while mixing with a hand mixer. The wet mass obtained was passed through a No. 25 sieve and then air dried. The dried granules were passed through a No. 30 sieve. The granules obtained were mixed with additional material for compression as indicated in Table 3.

The resulting mixture was compressed into tablets on a 3/8 inch die by a single punch tablet press (EK-0, Korsch, Germany). The weight of each tablet was 200 mg. The average disintegration time was 26 seconds and the tablet hardness was 22 N. When the degree of fracture test was conducted according to the US Pharmacopoeia, the degree of fracture was 1.12%.

Example 17

ingredient:

Loratadine 29.96 g

Mannogem EZ Spray 352.05 g

Advantose FS 95 Fructose (SPI Pharma) 117.35 g

Loratadine, Advantose FS 95 fructose and Mannogem EZ spray were mixed together and 99.87 g of 50% sucrose solution was added while mixing with a hand mixer. The wet mass obtained was passed through a No. 25 sieve and then air dried. The dried granules were passed through a No. 30 sieve. The granules obtained were mixed with additional raw materials required for the compression shown in Table 4 below.

The resulting mixture was compressed into tablets on a 3/8 inch die by a single punch tablet press (EK-0, Korsch, Germany). The weight of each tablet was 200 mg. The average disintegration time was 30 seconds and the tablet hardness was 26 N. When the degree of fracture test was conducted according to the US Pharmacopoeia, the degree of fracture was 1.23%.

Example 18

ingredient:

Loratadine 7.29 g

Mannogem EZ Spray 117.56 g

Loratadine and Mannogem EZ spray were mixed together and 48.0 g of 50% sucrose solution was added while mixing with a hand mixer. The wet mass obtained was passed through a No. 25 sieve and then air dried. The dried granules were passed through a No. 30 sieve. The granules obtained were mixed with the additional raw materials required for compression shown in Table 5 below. (This example requires an additional binder solution and may cancel out the properties of surface, mouth feel, hardness and degree of fracture. Mannogem EZ illustrates the use of Mannogem EZ as component 1 and component 2 because it is porous in addition to improving water permeability.)

The resulting mixture was compressed into tablets on a 3/8 inch die by a single punch tablet press (EK-0, Korsch, Germany). The weight of each tablet was 200 mg. The average disintegration time was 35 seconds and the tablet hardness was 23 N. When the degree of fracture test was conducted according to the US Pharmacopoeia, the degree of fracture was 1.84%.

Example 19

ingredient:

Advantose 100 Maltose (SPI Pharma) 31.21 g

Mannogem EZ Spray 96.63 g

Advantose 100 maltose (component 1) is a spray dried disaccharide carbohydrate. 28.16 g of 50% sucrose solution was added while advantose 100 maltose and Mannogem EZ spray were mixed together and mixed with a hand mixer. The wet mass obtained was passed through a No. 25 sieve and then air dried. The dried granules were passed through a No. 30 sieve. The granules obtained were mixed with additional raw materials required for the compression shown in Table 6 below.

The resulting mixture was compressed into tablets on a 3/8 inch die by a single punch tablet press (EK-0, Korsch, Germany). The weight of each tablet was 200 mg. The average disintegration time was 38 seconds and the tablet hardness was 18.5 N. According to the US Pharmacopoeia, the degree of fracture was 1.73%.

The invention has been described with reference to specific embodiments for purposes of illustration and description. It should be noted that various improvements and modifications of the invention can be made within the scope of the appended claims.

Claims (57)

A tablet that can be rapidly melted in the oral cavity, comprising a plurality of highly plastic granules, wherein the granules are prepared using a porous plastic material, a water penetration enhancer, and a binder at a concentration of 20-85%. The porous plastic material is a material that exhibits plastic deformation when 500 mg of material is compressed to a pressure of less than 1,500 pounds in a 0.5 inch diameter die, and the water penetration enhancer is in contact with a 0.5 ml droplet provided on a flat surface where the droplet does not spread. A tablet that is a material that exhibits complete wetting of a 200 mg tablet formed at 300 pounds in a 0.5 inch diameter die within 60 seconds of cold. The tablet of claim 1 further comprising an active pharmaceutical ingredient or dietary supplement. delete The tablet of claim 1, wherein the porous calcined material comprises 1% to 95% of the tablet weight. delete The tablet of claim 1, wherein the water penetration enhancer comprises 1% to 95% of the tablet weight. The tablet of claim 1, wherein the binder ensures that the particles of the porous plastic material and the water penetration enhancer are sufficiently adhered to each other to prevent particle separation and to improve granular adhesion at low pressures used to form tablets. The tablet of claim 1, wherein the binder comprises 1% to 90% of the weight of the tablet. The tablet of claim 1, wherein the porous plastic material and the water penetration enhancer are the same material. The tablet according to claim 2, wherein the active pharmaceutical ingredient is crystalline, microcrystalline or amorphous. The tablet of claim 2, wherein the active pharmaceutical ingredient is coated with one or more excipients. The method of claim 1, wherein the porous plastic material is maltodextrin, dextrin, ethylcellulose, gum arabic, xanthan gum and derivatives thereof, guar gum and derivatives thereof, seaweed gum, carrageenan, dextran, gelatin, alginate, pectin , Homopolymers or copolymers of starch and starch derivatives (such as hydroxypropyl starch or carboxymethyl starch), cellulose esters (such as carboxymethylcellulose or cellulose ether hydroxyethyl-methylcellulose), unsaturated acids (such as acrylic acid or salts thereof) , Homopolymers or copolymers of unsaturated amides (such as acrylamides), homopolymers or copolymers of ethylene imine, vinyl polymers (such as poly (vinyl alcohol)), vinyl esters (such as vinylpyrrolidone, vinyloxazolidone, vinyl Homopolymers or copolymers of methyloxazolidone, vinylamine, and vinylpyridine) Coalesce, alkylglycol and polyalkylene oxides (such as polyethylene oxide), oxyethylene alkylethers, dexates, dextrose, fructose, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, erythritol, xr Selected from the group consisting of silitol, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, calcium sulfate, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate and carboxymethylcellulose-calcium salt refine. The method of claim 1, wherein the water penetration enhancer is dexrate, dextrin, dextrose, fructose, lactitol, lactose, maltitol, maltose, mannitol, mannose, sorbitol, sucrose, erythritol, xylitol, microcrystalline Tablets selected from the group consisting of cellulose, silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, calcium sulfate, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, carboxymethylcellulose-calcium salt and combinations thereof. The method of claim 1, wherein the binder is dexrate, dextrin, dextrose, fructose, lactitol, lactose, maltitol, maltose, mannitol, mannose, sorbitol, sucrose, erythritol, xylitol, starch, gelatin, Acacia, alginic acid, sodium alginate, cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polydextrose, poly (acrylic acid), CARBOMER, poly (ethylene Oxide) and povidone. The method of claim 2, wherein the active pharmaceutical ingredient is an antimigraine drug, an antirheumatic drug, a non-steroidal anti-inflammatory drug, an opioid, an anti-mycobacterial drug, an antiparasitic drug, an antiviral drug, a beta-lactam , Macrolide antibiotics, fluoroquinolone, tetracycline, alkylating agents, anti-metabolites, hormonal drugs and antagonists, mitosis inhibitors, immunosuppressants, arrhythmia drugs, antihypertensive drugs, beta-adrenergic drugs, calcium -Channel blockers, hypolipidemic drugs, nitrates, anticonvulsants, antidepressants, anti-anxiety drugs, sedatives, hypnotics, neurodegenerative diseases drugs, eye drops drugs, antipepsins, bismuth salts, antiseptics, laxatives, coagulants and anticoagulants, hematopoietic drugs, Antidiabetic drugs, birth control pills, thyroid and antithyroid drugs, diuretics, electrolytes, gout medications, asthma medications, antihistamines, coughs, colds and flu medications, and nutrition Tablets belonging to a drug selected from the group consisting of supplements. 3. The active ingredient according to claim 2, wherein the active ingredient is loratadine, desloratadine, cetirizine, chlorpheniramine, diphenhydramine, fexofenadine, dextromethorphan, guipensin, pseudoephedrine, acetaminophen, aspirin, ibuprofen, ketopro Pens, indolmethacin, pyroxam, celecoxib, fentanyl, hydrocodone, oxycodone, cyclosporin, methotrexate, valacyclovir, amoxicillin, sepisim, azithromycin, methotrexate, tamoxifen, sirolimus, Tacrolimus, digoxin, captopril, clonidine hydrochloride, minoxidil, reserpin, metoprolol, propranolol, diltiazem, felodipine, nifedipine, fenofibrate, atorvastatin, lovastatin, pravastatin, simvastatin, nitroglycerin, Phenobarbital, phenytoin, mirtazapine, bupropion, fluorocetin, parosetin, sertraline, venlafaxine, Lorpromazine, risperidone, chlordiazepoxide, diazepam, carbidopa and levodopa, sodium bicarbonate, calcium carbonate, cimetidine, famotidine, ranitidine, lansoprazole, omeprazole, diphenhydramine, ondansetron, dexamethasone, bisacodeyl, lo Feramide, phytonadione, ticlopidine, warfarin, iron salt, methylprednisolone, prednisone, metformin, nateglinide, repaglinide, tolbutamide, glypide, iodide, amylolide, furosemide Tablet, which is a drug selected from the group consisting of theophylline, folic acid, vitamins and caffeine. A tablet according to claim 1 having a weight in the range of 5 mg to 5,000 mg. The tablet of claim 17 having a weight in the range of 50 mg to 500 mg. The tablet of claim 1 which melts in less than 90 seconds in the mouth. The tablet of claim 19 that melts in less than 60 seconds in the mouth. The tablet of claim 1, further comprising at least one additional component selected from the group consisting of surfactants, superdisintegrants, ultraporous hydrogel particles, blowing agents, lubricants, flavoring agents, and coloring agents. Combining the porous plastic material and the water penetration enhancer to form a mixture thereof; Treating the mixture with a binder at a concentration of 20-85% to form agglomerated particles agglomerates; Sieving and / or drying the aggregated particles to separate the plurality of highly calcined granules; And In the method of producing a quick-melt pharmaceutical tablet comprising the step of compressing the high-plastic granules under low pressure to obtain a quick melt pharmaceutical tablet, The porous plastic material is a material that exhibits plastic deformation when 500 mg of material is compressed to a pressure of less than 1,500 pounds in a 0.5 inch diameter die, and the water penetration enhancer is in contact with a 0.5 ml droplet provided on a flat surface where the droplet does not spread. A material that exhibits complete wetting of a 200 mg tablet formed at 300 pounds in a 0.5 inch diameter die within 60 seconds. The method of claim 22, further comprising intimately combining an active pharmaceutical ingredient with the porous plastic material, water penetration enhancer and / or binder prior to mixing the porous plastic material and the water penetration enhancer. The method of claim 22, wherein the porous plastic material is water soluble or water dispersible. delete delete The method of claim 22, wherein the binder is provided in liquid or semisolid form. The method of claim 22, wherein the binder is dissolved in an aqueous solution or a mixture of water and an organic solvent prior to the treatment. 23. The method of claim 22 wherein compression is carried out using a tablet press under a compression pressure of less than 150 MPa. 30. The method of claim 29, wherein the compression pressure is less than 35 MPa. 31. The method of claim 30, wherein the compression pressure is less than 10 MPa. The method of claim 22 further comprising combining the high calcined granules with one or more additional ingredients prior to compacting. 33. The method of claim 32, wherein the at least one additional component is selected from the group consisting of surfactants, superdisintegrants, superporous hydrogel particles, blowing agents, lubricants, flavoring agents, and coloring agents. The method of claim 22, wherein the porous plastic material and the water penetration enhancer are the same material. 23. The method of claim 22, wherein the agglomerated particles are mixed using a high shear mixer, a low shear mixer or a fluid bed mixer. The method of claim 22, wherein the drying involves air drying, vacuum drying, oven drying, fluid bed drying, or microwave drying. A pharmaceutical tablet having rapid melting properties made by the method according to claim 22. The method of claim 22, further comprising intimately combining the active pharmaceutical ingredient with the high calcined granules prior to compaction. A pharmaceutical tablet having rapid melting properties made by the method according to claim 38. Treating the porous plastic material with a binder at a concentration of 20-85% to form a first mass of aggregated particles; Treating the water penetration enhancer with a binder at 20-85% concentration to form a second mass of aggregated particles; Separating the plurality of highly calcined granules by sieving, mixing and drying the mass of the aggregated particles; And In the method for producing a quick-melt pharmaceutical tablet comprising the step of compressing the high-plastic granules under low pressure to obtain a quick-melt pharmaceutical tablet, The porous plastic material is a material that exhibits plastic deformation when 500 mg of material is compressed to a pressure of less than 1,500 pounds in a 0.5 inch diameter die, and the water penetration enhancer is in contact with a 0.5 ml droplet provided on a flat surface where the droplet does not spread. A material that exhibits complete wetting of a 200 mg tablet formed at 300 pounds in a 0.5 inch diameter die within 60 seconds. 41. The method of claim 40, further comprising intimately combining the active pharmaceutical ingredient with a porous plastic material, water penetration enhancer, and / or binder prior to mixing the agglomerates of aggregated particles together. 41. The method of claim 40, wherein the porous plastic material is water soluble or water dispersible. delete delete 41. The method of claim 40, wherein the binder is provided in liquid or semisolid form. 41. The method of claim 40, wherein said binder is dissolved in an aqueous solution or a mixture of water and an organic solvent prior to said treatment. 41. The method of claim 40 wherein compression is performed using a tablet press under a compression pressure of less than 150 MPa. 48. The method of claim 47, wherein said compression pressure is less than 35 MPa. 49. The method of claim 48, wherein the compression pressure is less than 10 MPa. 41. The method of claim 40, further comprising combining the high calcined granules with one or more additional ingredients prior to compacting. 51. The method of claim 50, wherein said at least one additional component is selected from the group consisting of surfactants, superdisintegrants, superporous hydrogel particles, blowing agents, lubricants, flavoring agents, and coloring agents. 41. The method of claim 40, wherein the porous plastic material and the water penetration enhancer are the same material. 41. The method of claim 40, wherein the flocculated particles are mixed and treated using a high shear mixer, a low shear mixer or a fluid bed mixer. 41. The method of claim 40, wherein the drying involves air drying, vacuum drying, oven drying, fluid bed drying, or microwave drying. A pharmaceutical tablet having rapid melting properties made by the method according to claim 40. 41. The method of claim 40, further comprising the step of intimately combining the active pharmaceutical ingredient with the high calcined granules before compacting. A pharmaceutical tablet having rapid melting properties prepared by the method of claim 56.

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