TWM527766U - Solid soft orally-soluble tablet containing multi-unit carriers - Google Patents

Abstract

A solid soft orally-soluble tablet containing multi-unit carriers is provided. The tablet containing a core, a shell, and carriers carrying active substances, which is a solid or a liquid material having biological activities. The shell encapsulates the core, and the carriers are located in the core, the shell or both of them.

Description

Solid soft ingot containing multi-unit carrier

The present invention relates to an oral dosage form, and in particular to a solid soft oral dosage form.

With the advancement of preparation technology, the types of pharmaceutical preparations are becoming more and more diverse, from solid tablets to liquid medicines, from solvent-based to various controlled release dosage forms, which can be different depending on the desired drug action. the design of. However, many drugs have an unpleasant taste, so taking drugs is often a burden for the elderly and children.

The capsule is initially used as a dosage form for filling a drug, which can be used to quantify the dosage unit of the powdered or liquid drug, and can avoid the unpleasant taste of the drug. However, swallowing capsules has also become a burden for many swallowing disorders such as young children, children, the elderly, chronically ill patients and cancer patients.

In order to facilitate the swallowing disorder, the group has some pharmacological effects. Or a bioactive active substance or nutrient, a dosage form that can be chewed in the mouth is an attemptable direction. The following provides a solid soft-melt ingot containing a multi-unit carrier. After chewing, the solid soft-melt ingot will disintegrate or dissolve in the oral cavity, and release the active substance or nutrient carried by the carrier, so as to facilitate the body to absorb the active substance or Nutrients.

Accordingly, one aspect of the present invention is to provide a solid, soft, solubilized ingot containing a multi-unit carrier. The solid soft melt ingot described above comprises a core, a shell and a plurality of carriers. Where the outer casing is wrapped outside the core, the carrier is distributed in the core, the outer casing or both. The main material of the above core is sugar alcohol, edible gum or edible starch, and the sweetener used in the core is oligosaccharide or sugar alcohol. The above carrier is used to carry at least one active substance, and the active substance is a biologically active solid or liquid substance.

According to an embodiment, the above carrier comprises microparticles, microspheres, liposomes, sponge granules, dropping pills or any combination of the above.

According to an embodiment, at least a portion of the above described carrier has a coating.

According to an embodiment, a polymer is further included in the coating of the carrier, the polymer forming a mucus in the saliva to increase the time during which the active substance is retained in the oral cavity.

According to an embodiment, the polymer comprises a copolymer of methacrylic acid, a copolymer of aminoalkyl methacrylate, a copolymer of methacrylate, a copolymer of an alkyl methacrylate, and a hydroxypropane. Cellulose, hydroxypropylmethylcellulose or any combination thereof.

According to an embodiment, an absorption enhancer is further included in the core, the outer casing, the carriers, or any combination thereof.

According to an embodiment, the absorption enhancer comprises a surfactant, a fatty acid, an alcohol, an azone, a chitosan, a phospholipid, a red-lighting agent, and a piperine or any combination thereof.

According to an embodiment, the fatty acid described above comprises a saturated or unsaturated fatty acid having from 8 to 20 carbons.

According to an embodiment, the phospholipids described above comprise lecithin.

According to an embodiment, the surfactant described above comprises an anionic surfactant or a cationic surfactant.

According to an embodiment, the red-lighting agent comprises ginger powder or an oil extract thereof, paprika powder and or oil extract, cinnamon powder, peppermint oil, wintergreen oil or cinnamon oil.

According to an embodiment, an acid-base buffer is further included in the core, the outer casing, the carriers, or any combination thereof.

According to an embodiment, the acid-base buffer comprises a weak acid buffer comprising citric acid, malic acid, tartaric acid, phosphoric acid, lactic acid, gluconic acid, glucuronic acid, vitamin C, acetic acid or salicylic acid. .

According to an embodiment, the acid-base buffer includes a weak base buffer, and the weak base buffer includes hydrogencarbonate.

According to an embodiment, a viscous substance is further included in the carrier.

According to an embodiment, the viscous substance comprises gelatin, pectin, gum arabic, starch, polysaccharide, hydroxypropyl methylcellulose, protein, polypeptide, dead bacteria or any combination thereof.

The above novel content is intended to provide a simplified summary of the disclosure in order to provide a basic understanding of the disclosure. This Summary is not an extensive overview of the disclosure, and is not intended to identify key/critical elements of the novel embodiments or the scope of the invention. The basic spirit and other novel objects of the present invention, as well as the technical means and implementation aspects of the present invention, can be readily understood by those of ordinary skill in the art.

100‧‧‧solid soft ingots

102‧‧‧ core

104‧‧‧Shell

106‧‧‧ Carrier

The following and other objects, features, advantages and embodiments of the present invention will become more apparent and understood. 1 is a schematic cross-sectional view showing a solid soft-melting ingot containing a multi-unit carrier according to an embodiment of the present invention.

As described above, by using a multi-unit carrier in a solid soft-melting ingot to carry various active substances which are solid or liquid at normal temperature, the sweetness and aroma of the solid soft-melt ingot are used to treat the unpleasant taste of the active substance. Such as bitterness and astringency, etc., so that people with dysphagia can easily take various active substances.

Accordingly, a solid state soft-melt ingot containing a multi-unit carrier is provided. In the following description, the above-described exemplary structure of a solid state soft-melt ingot containing a multi-unit carrier and its exemplified manufacturing method will be described. In order to facilitate an understanding of the described embodiments, a number of technical details are provided below. Of course, not all embodiments require these technical details. In the meantime, some well-known structures or elements are only shown in the drawings in a schematic manner to appropriately simplify the drawing.

Structure of solid soft ingot containing multi-unit carrier

Because the soft candy will collapse and dissolve in the mouth after chewing for a period of time, even if its size is small enough, it can be swallowed directly. Therefore, if the active substance can be added to the soft candy to form a solid soft-mouthed ingot, the active substance can be released into the saliva during the chewing process. However, the use of the carrier is a viable solution for how the active material can withstand the various manufacturing conditions of the solid soft-melting ingot without deterioration. Accordingly, there is provided a solid state soft-melt ingot containing a multi-unit carrier and a process for the preparation thereof.

Depending on the type of coagulant used, the water content and the process, solid soft-melt ingots can be classified into the following types: soft chewable tablets, soft fast-disintegrating tablets, jelly jelly, elastic jelly and fast-dissolving soft candy. The shape can be determined into any shape as desired, and the simple shape can be ingot or spherical.

1 is a schematic cross-sectional view showing a solid soft-melting ingot containing a multi-unit carrier according to an embodiment of the present invention. At the 1st In the drawings, the shape of the solid soft-melting ingot 100 can be any desired shape, such as a sphere, a square, or any other desired shape. The structure of the solid soft-melting ingot 100 includes a core 102, a casing 104 surrounding the surface of the core 102, and a multi-unit active carrier 106 for carrying a variety of different active materials. The carrier 106 described above may be distributed within the core 102, the outer casing 104, or both.

The core 102 described above is essentially a soft candy containing a sweetener and a coagulant for fixing the shape. The core 102 has a water content of 5 to 30% by weight, for example, 10% by weight. In addition to the above sweeteners, various other sour agents, flavoring and taste stimulating agents, etc., which are flavoring agents, may be added. In addition, an absorption enhancer may also be added to increase the amount of oral absorption of the active substance. In addition, a weak acid type acid-base buffer may be added to allow molecules of certain active substances to be in an electrically neutral molecular state or free form to help penetrate the oral mucosa via the intracellular ( Intracellular) or intercellular pathways are absorbed.

The outer casing 104 may be of a single layer or a plurality of layers, and may be naturally formed by the core 102 after drying, or the core 102 may be additionally wrapped with a sugar coating, a film coating or a combination thereof to form the outer casing 104. Thus the material of the outer shell 104 includes flavoring agents such as sweeteners, sour agents, flavors and taste stimulants. Further, an absorption enhancer and a weak acid type acid-base buffer may be selectively added to the outer casing 104. Since the core 102 of the solid soft-melting ingot has a high water content, the outer casing 104 can prevent the cores 102 from sticking to each other, and can also stabilize the core 102. The amount of water prevents the core 102 from becoming hard. In addition, if the outer casing 104 has various opaque colors, it can also shield the active material located in the core 102 from light to avoid photochemical reactions. In addition, the outer casing 104 of various colors can also provide a more pleasing appearance.

The above carrier 106 contains an active substance, which may comprise any available biologically active chemical substance (such as health food, nutritional supplement or medicine) or biological substance (such as an enzyme, a cell) which is artificially synthesized, extracted from a natural substance or converted by a living organism. Or dead bacteria). Therefore, when the solid soft-melted ingot 100 is chewed, the carrier 106 can release a high concentration of the active substance in close proximity to the oral mucosa, thereby increasing the absorption of the active substance by the oral mucosa. In core 102, carrier 106 can be added in an amount up to 95% by weight.

The carrier 106 has a diameter of from about 0.03 to about 3,000 μm, which may range from 100 to 1,000 μm in accordance with an embodiment. Generally, when the diameter of the carrier 106 is less than 150 μm, the touch of the mouth and the tongue is hard to detect. When the diameter of the carrier 106 is less than 450 μm, it is difficult to be bitten by a tooth in a short time when chewing, so that a longer chewing time can be used to increase the absorption rate of the oral delivery system, so that it can be slowly released and slowly absorbed. The active substance can maintain a stable concentration of the active substance in the blood for a long period of time.

The above active substances include central type appetite suppressants, which may be, for example, African mango extract or bitter orange extract, wherein the bitter orange extract may also improve metabolism. The above active substance may, for example, also be an inducer of vitamin B, such as benfotiamine.

In addition, the carrier 106 may optionally further comprise an absorption enhancer, an acid-base buffer, a polymer capable of forming a mucus in saliva, and a viscous substance. Among them, the polymer and the viscous substance can increase the residence time of the active substance in the oral cavity to increase the oral absorption rate of various active substances. For example, it can increase the high water solubility and high mucosal permeability, low water solubility but high mucosal penetration rate and high water solubility of the biopharmaceutical classification system I, II and III, respectively. Oral absorption rate of active substances with low mucosal penetration rate.

Carrier form

The carrier 106 described above may be any carrier that can withstand the temperature and pressure of the solid soft-melt ingot manufacturing process and is sufficient to protect the active material, for example, pellets, sponges, and microspheres that meet the above conditions. Microsphere), dropping pill, liposome, or any combination of the above.

The above microparticles are microspheres or spheroids composed of a powder or a liquid of an active substance combined with excipients, which are usually less than 2.5 mm in size. The microparticles are generally prepared by extrusion spheronization, and the liquid lamination method, the powder lamination method or a combination thereof may be used to coat the core microparticles with a plurality of layers having different functions, and even the outermost layer may be further coated with a layer or Multi-layer coating to increase the stability of the active substance carried by it and control its internal activity The release of a substance or the purpose of its adsorption of foreign substances. The type of the above coating may be a sugar coating or a film coating.

In the case of sugar coating, the main material of the sugar coating may be, for example, a monosaccharide, a disaccharide, an oligosaccharide or a sugar alcohol, so that not only the taste can be improved, but also the stability and hardness of the microparticles can be increased.

In the case of a film coat, the types thereof can be, for example, a time-controlled release type, a pH-dependent type, a moisture-proof type, an elastic compression type, a long-acting type, and a large-intestine release type. The material of the film coat may be, for example, a polymer or a fatty acid having 5 to 50 carbons or an ester thereof. Therefore, in addition to increasing the stability of the particles, it is also possible to control the film coat to disintegrate under a specific environment, allowing the particles to contact the external environment and release the active material.

For example, when the film coat is elastic compression type (the material is usually elastic fiber or elastin), it can help the less compressive active substances (such as live bacteria, active proteins and polysaccharides, etc.) to resist solid state. The soft mouth-filled ingot is subjected to the pressure during the manufacturing process and molding, while still maintaining its activity.

For example, when the film coat is moisture-proof, it can also protect active substances (such as carnitine, etc.) which are sensitive to moisture and lose activity, so that the active substance can be maintained during the manufacturing process and storage of the solid soft-melt ingot. active.

For example, when the film coat is pH-dependent, such as an acid-insoluble type, the pH-sensitive active material can be protected so that the active material maintains its activity during the manufacturing process and storage of the solid soft-melt ingot.

For example, when the film coat is of a time-controlled release type, it can use a porous film coat which is insoluble in gastric juice and intestinal juice, and utilizes the number of holes to control the release rate of the active material. For example, when it is a sustained-release dosage form, the unpleasant taste such as bitterness, astringency, astringency, and the like released by the active substance per unit time can be reduced. In the case of an immediate release dosage form, the sweetness, sourness and a pleasant taste of the active substance can be released relatively quickly, competing with the active substance having an unpleasant taste to compete with the taste of the mouth. Therefore, the use of this machine can solve the natural odor of herbal extracts, food additives and drugs in most active substances.

The above sponge granule is a porous linear drug carrier, which is generally prepared by mixing an active material with a water-soluble substance and an appropriate amount of water and extruding it, and then forming a porous structure by various drying methods. Sponge granules. Since the sponge mitochondria have a porous structure, a composite structure can be formed with various fine particles, microlipids, and microspheres.

The material of the porous matrix of sponge mitochondria is typically cellulose, starch, water soluble materials or combinations thereof. The cellulose mentioned above may be, for example, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), microcrystalline cellulose ( Microcrystalline cellulose, MCC) or any combination thereof. The above water-soluble substance may be, for example, an amino acid or a sugar alcohol (having a molecular weight of less than 200 D). Since the sponge granules have a porous matrix, they can be used for adsorption and storage of liquids. Or a solid active substance such as an active substance dissolved in a liquid oil (such as a high-purity lutein and an extract or additive of zeaxanthin) or a fine powder of nanometer to submicron. Therefore, for the active substance in a liquid or suspension state, the structure of the sponge granule can be protected from being lost in the squeezing action of the solid soft-melting ingot manufacturing process. For finely divided solid active materials, the structure of the sponge mitochondria maintains its activity during processing and chewing. The sponge granules described above, like the microparticles, may also have coatings or film coats of various functions to increase the stability of the active substance, control the release of the active substance, and control the adsorption of foreign substances.

The microspheres described above are pharmaceutical carriers for dispersing the drug in a polymeric matrix, typically ranging in size from nanometers to micrometers, such as less than 800 microns. Common polymer matrix materials include starch, albumin, gelatin, chitosan, polylactide (PLA), and cyclic polylactate (CPL). The preparation method is generally to dissolve or disperse the active substance in the polymer solution, and then form a microsphere solid by spray drying.

The above-mentioned dropping pills are formed by uniformly mixing or dispersing a drug and an excipient into a liquid system, and then dropping into a difficult solution to form a film, so that a film is formed on the outer surface of the spherical body. Therefore, dropping pills are also a pharmaceutical carrier for carrying suitable active substances.

The above-mentioned liposome is a spherical vesicle structure which can be used for containing a drug inside. Microlipids can exist in liquid form The pores of the granules, microspheres or sponge granules may be present in the body of the microspheres and the dropping pills by processing.

As described above, the use of the carrier 106 to carry the active material and thus to the solid soft-melt ingot has at least the following advantages. First, the release period of the active substance can be increased. For example, when the active material is used as a powder, the release period is generally less than 5 minutes; if the diameter is 1 mm, the release period is about 10 to 15 minutes; if the diameter is 0.45 mm, the release period is It is about 7.5~10 minutes.

Second, the carrier 106 can increase the chemical structural stability of the active material having an unstable chemical structure. For active substances with unstable chemical structure, whether active materials sensitive to oxygen, moisture, light, temperature, pressure or other factors, various characteristics of the carrier 106 can be modified in various ways to protect various kinds of materials. The active substances with different characteristics will not lose their activity during the preparation of the solid soft-melting ingot and during storage, and will exert its full effect when chewing the solid soft-melting ingot.

Again, the carrier 106 can be used to carry active materials that are not suitable for placement together. For example, active substances that undergo a chemical reaction to destroy their activity or produce toxicity after being contacted with each other can be carried by different carriers 106, respectively, so that they can be prevented from each other during the production of the solid soft-melted ingot and during storage. It will be in contact to maintain its original activity until it is fully functional when chewing a solid soft-melt ingot.

Material of each component

The above coagulants are usually used as sugar alcohols, edible starches, edible gums or any combination of the above. The above sugar alcohol may be, for example, mannitol. Common edible starches are, for example, manioc starch, corn starch, potato starch, and uncooked rice starch. The commonly used edible gum can be divided into animal glue and vegetable glue according to the source. Common animal gums are gelatin, donkey-hide gelatin and fish gelatin. Common plant gums are agar, carrageenan, alginate jelly, gum arabic, guar gum, cellulose, carob Carob fruit, glutinous rice glue, β-glucan, pectin, Acacia gum, and xanthan.

The above sweetener may be, for example, a monosaccharide, a disaccharide, an oligosaccharide, a sugar alcohol or any combination of the above. The monosaccharide may be, for example, a five-carbon sugar or a six-carbon sugar. The common five-carbon sugars are arabinose and xylose. The common six-carbon sugars include idose, glucose, fructose and galactose. The disaccharide can be, for example, sucrose, lactose, maltose or trehalose. Oligosaccharides usually consist of 3-9 monosaccharide units, such as fructooligosaccharides, galactooligosaccharides, polyisomaltose, soy oligosaccharides or xylooligosaccharides. The sugar alcohol is usually formed by reduction of an aldehyde group or a ketone group of a sugar molecule to an alcohol group, and may be, for example, glucose alcohol, xylitol, sorbitol, maltitol, erythritol, lactitol. Or mannitol.

The main function of the sweetener is to provide the sweetness of the solid soft-melted ingot, some sweeteners also have the effect of assisting coagulation, and some sweeteners have other physiological functions. For example, some oligosaccharides or sugar alcohols have functions similar to water-soluble dietary fibers, which can promote the health of the gastrointestinal tract and help to probiotics in the intestine. Sugar alcohols can help diabetics control blood sugar and help obese patients control caloric intake.

A flavoring agent other than a sweetener may be any usable sour agent, flavor, taste stimulant, salty agent, or any combination thereof. The sour agent may be, for example, citric acid, malic acid, lactic acid, gluconic acid or the like. The flavors can be, for example, various natural fruit flavors, edible plant flavors, and edible artificial flavors. The taste stimulating agent includes a cooling agent and a red-lighting agent, wherein the cooling agent is, for example, mint, and the red-lighting agent may be ginger powder or an oil extract thereof, paprika or oil extract, pepper powder or oil extract, cinnamon powder, Peppermint oil, winter green oil or cinnamon oil. The salty agent can be a salt. The most common ones can be, for example, natural juices or milk.

The above acid-base buffers can be classified into two types: weak acid type and weak base type. The weak acid type acid-base buffer may be, for example, citric acid, malic acid, tartaric acid, phosphoric acid, lactic acid, gluconic acid, glucuronic acid, vitamin C, acetic acid or salicylic acid. In addition to controlling the pH of the oral cavity and increasing the solubility of weak acid or weak base actives, the weak acid acid-base buffer can also reduce the taste sensitivity to odors (such as bitterness) and assist certain The molecules of the active substance are in an electrically neutral free state so that they penetrate the oral mucosa and are absorbed. Weak base Types of acid-base buffers include bicarbonates such as sodium bicarbonate or potassium bicarbonate. In addition to being used to control the pH value in the oral cavity, the weak base type acid-base buffer can also stabilize some active substances, and if it can produce gas, it can also increase the release rate of the active substance. When a solid soft-melt ingot is required to be added with both a weak acid type and a weak base type buffer, the weak acid type and the weak base type must be present in different positions of the solid soft-melt ingot. The most common case is the presence of a weak acid in a solid soft-smelting ingot, a multi-unit carrier, and a weak base present in the carrier.

The above-mentioned polymer capable of forming a mucus in saliva is mainly used for forming a coating of the carrier 106, and the material thereof includes a methacrylic acid copolymer and an aminoalkyl methacrylate copolymer. , methacrylate copolymer, alkyl methacrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose Or any combination thereof. The above copolymer of methacrylic acid may be, for example, poly(methacrylic acid-co-ethyl acrylate) 1:1 [poly(methacrylic acid-co-ethyl acrylate) 1:1], poly(methacrylic acid-co- Methyl methacrylate) 1:1 [Poly (methacylic acid-co-methyl methacrylate) 1:1], poly(methacrylic acid-co-methyl methacrylate) 1:2 [Poly (methacylic acid-co- Methyl methacrylate) 1:2] or poly (acrylic acid) Ester-co-methyl methacrylate-co-methacrylic acid 7:3:1 [Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1]. The above coating materials can be passed through different processing coating steps to form different film coating layers or outer skin layers.

The above viscous substance may be, for example, gelatin, pectin, acacia, starch, polysaccharide, hydroxypropylmethylcellulose, protein, polypeptide, dead bacteria or any combination thereof. The above starch may be, for example, corn starch, tapioca starch, yam starch, sweet potato starch or raw rice starch. The source of the polysaccharide may be, for example, plant extraction or fermentation by yeast or fungi. The above protein may be, for example, collagen or glycoprotein.

Preparation method of multi-unit carrier solid soft oral ingot

The preparation method of the solid soft-smelting ingot core 102 containing the multi-unit carrier can be carried out by a mold method or a tableting method.

In the mold method, the step of mixing the mixture is first carried out, and the desired raw materials (sweetener, coagulant, carrier, and other desired additives) are uniformly mixed together by a stirring action. Then, the step of heating is carried out to boil the syrup. Next, after the syrup is cooled to a certain temperature in a larger mold, a solid is formed, which is then cut or pressed to an appropriate size to form the core 102.

In the tableting method, the dry powder (sweetener, coagulant, carrier, and other required additives) of the desired raw materials are uniformly mixed, and then the tablet is used for ingoting, and then the water is externally raised. The content is formed into a core 102 by a specific processing procedure.

Finally, it is selected whether or not to wrap the icing or film coat containing the desired additive to form the outer casing 104 to complete the manufacture of the solid soft-melting ingot 100.

Embodiment 1:

In this embodiment, the solid weight of the solid soft-melted ingot per unit has a core weight of about 0.55 g and a square micro-ingot having a size of about 1.0 x 0.8 x 0.5 mm ³ . The coagulant is a mixture of gelatin and starch. The sweeteners are sucrose and maltitol, and the flavor is a caramel flavor. The carrier is a bitter orange extract compound microsphere, a vitamin C microsphere and an absorption enhancer microsphere having a weight ratio of 8:1:1, and the absorption enhancer used is a mixture of phospholipid serine and phospholipid choline in a weight ratio of 1:1. ).

In this embodiment, several different outer casings were prepared. The first three shells are primarily coatings formed from a mixture of maltitol and sucrose. According to other additives, it can be divided into the following three kinds of coatings: transparent single layer coating without adding pigment, single layer coating with caramel color added, light pink double coating (adding 1wt% to the first layer) Calcium pyrophosphate, the second coating is a pale pink coating containing 0.5% by weight of anthocyanin grape seed extract). The fourth shell is a single layer coating of melted dark chocolate. After the outer shell was added, the weight gain of the solid soft-melt ingot was about 0.15 g (single layer), 0.23 g (double layer), and 0.18 g (chocolate). The materials used in this example are listed in Table 1 below. As can be seen from the above and Table 1, even if the same core material, the outer casing can still There are many variations.

Further, in this example, the content of the carrier in the solid solution core was also changed, and the mouthfeel was tested, and the results obtained are shown in Table 2 below. It can be seen from the results of Table 2 that the higher the content of the carrier, the softer the mouthfeel of the solid soft-melted ingot.

*The composition of the absorption enhancer is phospholipid serine and phosphatidylcholine in a weight ratio of 1:1.

Embodiment 2:

In this embodiment, the coagulant is changed to a mixture of pectin and gum arabic belonging to vegetable gum, and the core is shaped by replacing the gelatin which is conventionally used. The solid soft-melting ingot has a core size of about 1.0 x 0.8 x 0.5 mm ³ square and a weight of about 1.0 g. The carrier used was a bitter orange extract compound microsphere in an amount of 10% by weight. The outer shell is primarily a single layer coating formed from a mixture of maltitol and sucrose. The materials used in this example are listed in Table 3 below.

Embodiment 3:

In this example, the ingredients are shown in Table 4 below, but the coagulant was changed to mannitol, and the sweetener was changed to sorbitol, maltitol, fructooligosaccharide and malto-oligosaccharide available to diabetic patients. The carrier used was a bitter orange extract compound microsphere in an amount of 10% by weight.

Embodiment 4:

In this example, the ingredients used are shown in Table 5 below, in which the carrier was changed to a benzenephosphine thiamine microsphere, a vitamin C microsphere, and an absorption enhancer microsphere having a weight ratio of 8:1:1. The above components of the phenylphosphine sulfide microspheres are phenylphosphine sulfide, microcrystalline cellulose, instant coffee powder, hydroxypropylmethylcellulose and sucralose in a weight ratio of 70:10:8:1.5:0.5. Moreover, the phenylphosphine thiamine microspheres can be further immersed in a solution of syrup or other sweetener to allow the syrup or sweetener solution to penetrate into the phenylphosphine thiamine microsphere. In the pores of the ball.

In this embodiment, Benfotiamine, which is used to improve the clinical treatment side effects of diabetic patients, has an odor which can be modified by the raw material and release characteristics of the phenylphosphine thiamine microspheres, together with a solid soft-melted ingot and The sweeteners and flavors added to the core can almost completely mask the odor of phenylphosphine sulfide.

* The composition of the phenylphosphine sulfide microspheres is phenylphosphine sulfide, microcrystalline cellulose, instant coffee powder, hydroxypropylmethylcellulose and sucralose in a weight ratio of 70:10:8:1.5:0.5.

Embodiment 5:

In this example, the active material used was an oily solution of 20% by weight of lutein ester, and the details of the materials used are shown in Table 6 below. After preparation of lutein ester microspheres, the microspheres remain good enough to maintain lutein even though they have a hardness greater than 7 H, even after 100 ° C and 400 Kg/cm ² high temperature and high pressure processes of solid soft-melting ingots. The stability of the ester oily solution.

* The lutein ester microspheres are composed of a lutein ester oil solution, microcrystalline cellulose, and hydroxylpropyl methyl cellulose (HPMC) in a weight ratio of 30:65:5.

Example 6:

Vitamin B2 undergoes an isomerization reaction in an acidic and watery environment, and thus discolors and has an odor. In this example, the starting material of the carrier of the experimental group was vitamin C, vitamin B2 and microcrystalline cellulose in a weight ratio of 75:5:20. The control group was a mixture of the above materials, and the weight ratio of vitamin C, vitamin B2 and microcrystalline cellulose was also 75:5:20.

The solid soft-mouthed ingot is prepared by taking 100 g of the carrier or the above-mentioned raw material mixture, respectively adding 60 g of gelatin, 270 g of sucrose and 300 g of water, stirring and heating to about 100 ° C to form a uniform syrup mixture. After cooling to room temperature at room temperature and drying, the refrigerating was continued for another 12 hours. After taking out, it was cut into a square having a size of 1.0 × 0.8 × 0.5 cm ³ to obtain a solid soft-melt ingot. The raw materials of the control group were also subjected to the same process conditions to prepare a solid soft-melt ingot. The various materials used in this example are listed in Table 7 below.

In Table 8 below, the manufacturing process and the change in appearance after 14 days of storage were observed to understand the preparation and storage stability of the solid soft-melted ingot. From the results of Table 8, it can be seen that when the vitamin B2 is placed in a carrier, it is not easily deteriorated even in an acidic water environment, and its stability is increased.

* Ingredients are vitamin C, vitamin B2 and microcrystalline cellulose in a weight ratio of 75:5:20.

Example 7:

In this embodiment, several different oral release actives are tested and the length of time in which the active is sustained in the oral cavity is compared. The active substance used herein is vitamin C, so it is a test of the length of time that the sour taste stays in the oral cavity. Rinse the drinking water before testing to maintain sufficient and constant humidity and a constant temperature in the mouth. The dosage forms tested in the respective experimental examples are described below, and the results obtained are shown in the following table.

The experimental group was a solid soft-mouthed ingot containing microspheres of vitamin C and vitamin B2. The raw material of the microspheres was the same as the microspheres of the above-mentioned Example 11. The other raw materials for the solid soft-melting ingot are sucrose, gelatin, starch and water in a weight ratio of 7:1:1:1. The solid soft-mouthed ingot has a size of 1.0 x 0.9 x 0.6 cm ³ and a weight of about 0.65 g. Each solid soft-melted ingot contains 17% by weight of vitamin C and 1.1% by weight of vitamin B2. See Table 9 below for details.

* Ingredients are vitamin C, vitamin B2 and microcrystalline cellulose in a weight ratio of 75:5:20.

In the control group, there are sublingual absorption capsules, sublingual ingots, orally disintegrating ingots and buccal ingots as described below.

The capsule of the sublingual absorption capsule has six pores having a diameter of about 0.37 mm, and the contents are 115 mg of lactose and 115 mg of vitamin C.

The sublingual ingot has a diameter of about 6 mm and contains 115 mg of lactose and 115 mg of vitamin C.

The otoposide contains 100 mg of lactose, 100 mg of vitamin C and 30 mg of disintegrating agent (sodium starch glycolate).

The buccal ingot has a diameter of about 10 mm and contains 115 mg of lactose and 115 mg of vitamin C.

The results obtained are shown in Table 10 below.

^a with the tongue touch sense agent dissipating time

^b with tongue tactile sensation dissipating time

Part ^c particles swallowed with saliva

Example 8:

In this embodiment, several different oral release actives are tested, comparing the rate of absorption of the active substance with the length of time during which the effective concentration in the blood is maintained. The active substance used here is vitamin B2, so the time in which the vitamin B stays in the body can be known from the color of the urine.

The experimental group was a solid soft oral ingot, and the carrier used was a sponge granule or microsphere of a vitamin B2 compound. Each 450 mg of solid soft-melted ingot contains 25 mg of vitamin B2.

The preparation method of the above vitamin B2 compound sponge granules is as follows As described below. Vitamin B2 and sucralose were first dissolved in a glyceride at 60-70 ° C. The weight ratio of vitamin B2, sucralose to glyceride was 50:5:45, and the total weight was 500 g. After homogeneous mixing, the mixture was allowed to cool rapidly to form a thin yellow mass. The obtained yellow thin piece was pulverized by a pulverizer and passed through a No. 40 sieve to obtain a yellow fine powder. Next, the yellow fine powder and the glycine acid were mixed, and the weight ratio of the yellow fine powder to the glycine was 3:7. Then, 10 wt% of distilled water was added to the total weight of the raw material by a single-screw extruder, and then extruded, and placed in a moisture-proof box for about 48 hours to form a sponge-containing granule containing vitamin B2 (15 wt%).

The preparation method of the above vitamin B2 compound microspheres is as follows. The vitamin B2, sucralose, microcrystalline cellulose, and hydroxypropyl methylcellulose in a weight ratio of 50:5:40:5 are mixed, squeezed and rounded, and dried to form a vitamin B2 compound microsphere.

The control group was a sublingual absorption capsule and an orally disintegrating ingot. The sublingual absorption capsule is a No. 3 capsule having six holes having a diameter of about 0.67 mm. Each capsule was filled with 230 mg of vitamin B2 compound sponge granules containing 25 mg of vitamin B2. The above-mentioned orally disintegrating tablet was prepared by mixing 230 mg of a vitamin B2 preparation (a mixture of glyceride and vitamin B2), 30 mg of sodium starch glycolate and 40 mg of lactose. The tablet has a diameter of 10 mm, a thickness of 2.5 mm, and a hardness of about 4 H.

The test method is to let the same person drink 300mL of drinking water at 9:00 in the next five days, and then take the vitamin B2 of various oral dosage forms of Experimental Examples 3-1 to 3-5. Then, at different points in time (09:00, 09:15, 09:30, 10:30, 13:00) 15:00) Test urine color.

The urine is compared by the color method, and the standard of the color method is shown in Table 11. The standard E is 09:00 urine when no vitamin B2 is taken, and the standard A~D is standard E and then added with different amounts of vitamin B2. According to the color of the standard listed in Table 11, the urine test results are shown in Table 12 below.

From the results of Table 12 above, it can be seen that the oral soft-dissolved ingots and the carrier are microspheres, and the urine begins to turn yellow in 90 minutes, indicating that the vitamin B2 is mostly absorbed by the small intestine before being metabolized. Excreted through the kidneys. In the case of a sublingual absorption capsule and a solid soft-melting ingot of the carrier which is a fast-dissolving sponge granule, the urine starts to yellow in 15-30 minutes. It is shown that both are absorbed by the sublingual mucosa and quickly enter the circulatory system, so the rate of excretion by the kidneys is faster.

It can be seen from the above that the active substance dissolved in the saliva can be locally applied to the oral cavity or further absorbed by the oral mucosa (including the buccal mucosa, the sublingual mucosa and the oral vestibule). Absorption of the active substance by the oral mucosa has the following advantages, for example, an onset can be produced within 5 minutes, and a small dose can be used to achieve an effective concentration in the blood and a maximum blood concentration, without passing through the liver. And the first metabolism of the small intestine enters the systemic circulation to produce pharmacological effects, which can be deactivated without the decomposition and digestion of gastric acid and gastrointestinal digestive enzymes, and can be transported and circulated directly through the superior vena cava system such as the jugular vein after absorption. To tissues such as the heart, brain, lungs, and skin.

Although the present invention has been disclosed in the above embodiments, it is not intended to limit the present invention. Any one skilled in the art can make various changes and retouchings without departing from the spirit and scope of the present invention. The scope is subject to the definition of the scope of the patent application attached.

100‧‧‧solid soft ingots

102‧‧‧ core

104‧‧‧Shell

106‧‧‧ Carrier

Claims (10)

A solid soft oral ingot containing a multi-unit carrier, comprising: a core, the main material of which is sugar alcohol, edible gum or edible starch, the core sweetener is oligosaccharide or sugar alcohol; And a plurality of carriers carrying at least one active substance distributed in the core, the outer shell or a combination thereof, wherein the active substance is a biologically active solid or liquid substance. The solid soft-melt ingot according to claim 1, wherein the carrier comprises microparticles, microspheres, liposomes, sponge granules, dropping pills or any combination thereof. The solid soft-melted ingot of claim 1 wherein at least a portion of the carriers have a coating. The solid soft-melted ingot according to claim 3, further comprising a polymer in a coating of the carrier, the polymer forming a mucus in the saliva to increase the time during which the active substance is left in the oral cavity. The solid soft-melted ingot according to claim 4, wherein the polymer comprises a copolymer of methacrylic acid, methacrylic acid a copolymer of an aminoalkyl ester, a copolymer of a methacrylate, a copolymer of an alkyl methacrylate, hydroxypropylcellulose, hydroxypropylmethylcellulose or any combination thereof. The solid soft-melt ingot of claim 1 further comprising an absorption enhancer located in the core, the outer shell, the carriers, or any combination thereof. The solid soft-melting ingot according to claim 6, wherein the absorption enhancer comprises a surfactant, a fatty acid, an alcohol, an azone, a chitosan, a phospholipid, a red-lighting agent, and a piperine or any combination thereof. The solid soft-melted ingot as claimed in claim 1 further comprising an acid-base buffer in the core, the outer casing, the carriers or any combination thereof. The solid soft-melted ingot as claimed in claim 1 further comprising a viscous substance in the carrier. The solid soft-melted ingot according to claim 9, wherein the viscous substance comprises gelatin, pectin, acacia, starch, polysaccharide, hydroxypropylmethylcellulose, protein, polypeptide, dead bacteria or any combination thereof. .