TWI406679B - Oral disintegrating tablet containing a high dosage of active ingredients - Google Patents

Abstract

The present invention provides an oral disintegrating tablet designed to be dissolved on the tongue rather than swallowed whole, which contains active ingredients at a high amount of 20 wt% to 80 wt%, and provides a new drug dosage form different from the traditional tables and known ODTs containing a limited amount of active ingredients.

Description

Oral ingot containing high dose of active substance

The present invention relates to improvements in mouth collapse tablets.

Oral disintegration dosage forms, also known as "orally disintegrating tablets" or "rapid disintegrating tablets", are preparations that automatically disintegrate into innumerable particles within 60 to 90 seconds of the tongue. Because the disintegration of the mouth-breaking ingot is fast, absorption is rapid, and there is no need to drink water after taking it, it is very suitable for some special patients, such as mental illness, oral inflammation and ulceration, difficult to swallow or epileptic patients, and elderly, children, etc.

At present, many drugs have been developed as oral ulcers, such as antiulcer drugs (such as Lansoprazole), antihistamines (such as Loratadine), antipsychotic drugs (Risperidone), anti-asthmatic drugs (such as Salbutamol and ibuprofen, Aspirin), etc. An antipyretic and analgesic old drug, but the active substance (pharmaceutically active substance) of the mouth-disintegrated tablet is present in a trace amount. In the preparation method and excipient formula of the current prior art mouth-breaking ingot, when the active substance content is too high (20% by weight or more), the orally disintegrating ingot may not be formed, or may not be disintegrated in 60 to 90 seconds. In addition, some drugs or active substances, such as vitamin B group, have a bad taste such as bitterness, astringency or odor when made into a high-dose mouth-breaking tablet, and the intention to take it is lowered.

There is a need for an orally disintegrating tablet that rapidly disintegrates but contains a high dose of active material while improving the unpleasant mouthfeel.

SUMMARY OF THE INVENTION The object of the present invention is to provide an orally disintegrating tablet containing a high dose of an active substance, but still rapidly disintegrating and improving the loss of unpleasant mouthfeel. The invention mainly improves the formulation of the disintegrating agent and the diluent, thereby greatly increasing the content of the active substance in the mouth-breaking ingot, so as to facilitate the taking of a special patient or an elderly person or a child, for example, a nutritional supplement.

The present invention provides an orally disintegrating ingot comprising from about 20% to 80% by weight of active substance, further comprising from about 2% to 10% by weight of disintegration And a diluent of from about 10% to about 75% by weight; wherein the disintegrating agent is mixed with from about 1% to 9% by weight of the blowing agent, and the total amount of the two does not exceed 10% of the total weight of the orally disintegrating ingot weight%.

The invention further provides an orally disintegrating tablet characterized by comprising about 20% to 80% by weight of an active substance, further comprising about 2% to 10% by weight of a disintegrating agent; and about 10% to 75% by weight of a dilution The diluent; wherein the diluent is a granulated lactose or a mixture of granulated lactose and starch.

As used herein, "% by weight", unless otherwise defined, refers to the total weight percent of the orally disintegrating ingot.

The term "orally ingot" as used herein refers to a solid dosage form that can be rapidly disintegrated within a certain period of time after being placed on the tongue. The disintegration of the tablet can be disintegrated or dissolved with only a little saliva. Special patients or users, especially those who have difficulty swallowing. One of the orally disintegrating ingots is characterized by complete collapse in a short period of time. According to an embodiment of the invention, it can completely collapse between 60 and 80 seconds. Further, according to another embodiment of the present invention, it is completely collapsed in 20 to 40 seconds.

The term "active substance" as used herein, ie, an ingredient that is intended to provide efficacy or provide efficacy, is a therapeutically effective drug, a physiologically active nutritional supplement or other substance that enhances the body's health benefits. For example, but not limited to: polyphenols, such as: tea polyphenols, red wine polyphenols; flavonoids (Flavon), such as: Rutin, Quercetin; Terpenes For example, curcumin; water-soluble vitamins, such as: vitamin C, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B9, vitamin B12, Choline, and amino benzene. Para-aminobenzoic acid; Fat-soluble vitamins, for example: vitamin D, vitamin K, vitamin E; antioxidants, such as: Free base and ester, beta-carotene , anthocyanins, blackcurrant extracts, resveratrol, etc.; amino acids (Amino acids), such as: glycine, arginine, valine, tryptophan, lysine, oxalic acid, carnitine (Carnitin); mineral (minerals), such as calcium salt, magnesium salt, zinc, iron; glycoside; saponin, for example: ginsenoside; organic acid, such as citric acid; oligopeptide (Oligopeptide), such as Soy hydrolyzed protein; polypeptide or protein, for example: ten peptide, milk protein and milk hydrolyzed protein, type II collagen; polysaccharide (polysaccharide), for example: hexose polysaccharide mixture; fatty acid; Alkaaloid, for example: Piperine; essential oils, for example: eucalyptus oil, juniper oil, sweet almond oil, geranium oil, rose essential oil, pine bark essential oil; plants, Chinese herbal medicines or extracts thereof, for example: Antrodia camphorata, Ginkgo biloba extract, Ganoderma lucidum, Garcinia Cambogia, Angelica, Maimendong , Chinese yam, licorice, cinnamon, rhubarb; probiotics, such as: Lactoacillus case , Bifidobacterium bifidum , Bifidobacterium Longum ; or natural source of animal Foods, for example: astaxanthin, glucosamine, chondroitin, propolis, royal jelly, hydrolyzed milk protein. The above active substance may be added with one or more active substances without affecting the collapse rate and preparation of the orally disintegrating tablet of the present invention.

The orally disintegrating ingot of the present invention can be prepared by using a disintegrating agent for use in an orally disintegrating ingot in the technical field to which the present invention pertains, with a swelling type disintegrating agent being preferred. The term "swellable disintegrating agent" as used herein is a chemical substance which can absorb moisture and cause solid expansion and collapse. The swelling type disintegrating agent suitable for use in the present invention may be one selected from the group consisting of Combination: Low-substituted Hydroxypropyl Cellulose, Sodium Starch Glycolate (SSG), Crospovidone (PVPP), Hydroxyxy Propionate (HydroXypropy Starch) Cross-linked Sodium Carboxymethyl Cellulose Sodium. According to an embodiment of the invention, the disintegrating agent is sodium sulphate (Sodium Starch Glycolate, SSG) or crospovidone (PVPP), or a combination thereof.

According to an embodiment of the present invention, the disintegrating agent comprises a mixing amount of about 2% by weight to 6% by weight of the swelling type disintegrating agent, and about 2% by weight to 6% by weight of the foaming agent, and the total amount of the two Not more than 10% by weight of the total weight of the orally disintegrating ingot.

As used herein, "foaming agent" is a gas-generating disintegrating agent or a foam-producing surfactant which contains a foaming component in the formulation, or which can produce carbon dioxide, or Its combination. The term "gas-producing disintegrating agent" as used herein refers to a composition comprising an acidic substance and an alkaline substance. When contacted with water molecules, the chemical reaction of acid-base neutralization can release carbon dioxide to generate bubbles, so that the tablet or the lozenge or The particles quickly collapsed. According to the present invention, the gas generating type disintegrating agent is a combination of sodium hydrogencarbonate and a group selected from one or more of the following: citric acid, malic acid, tartaric acid, phosphoric acid, lactic acid, gluconic acid, vitamin C, acetic acid and Water acid. According to an embodiment of the present invention, the gas generating type disintegrating agent is a composition comprising sodium hydrogencarbonate and citric acid. As used herein, "surfactant" refers to a surfactant which, when introduced into the air by mechanical force, produces a large amount of foam and aids in the disintegration of the tablet. According to the present invention, such a surfactant may be a combination of one or more selected from the group consisting of vitamin E, sodium laurate, caprylic acid, azone, sodium lauryl sulfate, and polyethylene glycol. .

As used herein, "diluent" refers to a substance which increases the fluidity and lubricity of the granules, reduces mechanical wear when preparing tablets, and has a hydrophilic substance, which simultaneously increases the disintegration of the troches, such as conventional techniques. Lactose or mannitol used. According to the present invention, a granulated lactose or a mixture of granulated lactose and starch is used as a diluent, and it is found to have an unpredictable effect of helping to disintegrate. As used herein, "granulated lactose" refers to a lactose having a circular crystal structure and having a particle size of from 50 μm to 200 μm. According to a particular embodiment of the invention, the granulated lactose has a particle size of 100 μm. According to the invention, the mixture of granulated lactose and starch is meant to comprise from 10% to 90% by weight of a mixture of granulated lactose and starch. Starches suitable for use in the present invention may be, but are not limited to, corn starch, potato starch, tapioca starch, sweet potato starch, and wheat starch. According to an embodiment of the invention, the starch is corn starch. According to another embodiment of the invention, the starch content of the granulated lactose to starch mixture is from 10% to 20% by weight based on the total weight of the diluent.

The present invention can be prepared into various suitable ingot shapes as needed, for example, a circular arc shape, a triangular arc shape, a platelet type (a disc shape in the middle recessed shape), a disk or a dome shape.

The term "mouthfeel" as used herein refers to the feeling of taste, smell and touch to the user. Many drugs or nutritional supplements have medium to medium Severe unpleasant taste (such as bitterness, sputum, spicy, etc.), smell (such as odor, astringency, medicinal taste, etc.) and touch (such as gritty, irritating, stagnation), affecting the user taking the tablet Willingness.

In order to improve the unpleasant mouthfeel, the orally disintegrating tablet of the present invention can be coated with the active material with obvious bitterness, odor or astringency, thereby effectively delaying the bad bitterness and astringency. It can cover unpleasant odor, astringency or medicinal taste. The coating material to which the present invention is applied is a combination of one or more selected from the group consisting of a saccharide, an alkanol, a fatty acid, a phospholipid, a glyceride, a wax, a plasticizer, a gum, for example, but Not limited to: cetyl alcohol, Glyceryl Dibehenate, beeswax, sucrose, shellac, gum arabic, ethyl fiber and hydroxypropyl methylcellulose. According to an embodiment of the present invention, a bitter-tasting active substance is pre-coated with glyceryl dibehenate, and a 10-point scale (0 is divided into no bitterness, 10 is extremely bitter) evaluation mode is employed, and the subject is invited. Providing a subjective feeling, the display has a significant effect of covering the bitterness.

According to the present invention, the orally disintegrating tablet of the present invention may optionally be added with other adjuvants such as flavoring agents, colorants, perfumes, lubricants or binders. Anyone skilled in the art may add an appropriate adjuvant to the orally disintegrating ingot of the present invention to improve its properties in accordance with conventional techniques and knowledge. According to an embodiment of the invention, the content of a suitable flavoring agent, colorant, perfume, lubricant or binder is from 0.1% by weight to 20% by weight.

At the same time, in the case that the orally disintegrating ingot of the present invention does not affect the original disintegration effect, one or more transdermal absorption agents or absorption enhancers which are commonly used in the formulation of oral preparations may be added as needed to improve the absorption of the active substance in the oral cavity. . According to an embodiment of the invention, the content of a suitable skin absorbent or absorption enhancer is from 1% by weight to 5% by weight.

The orally disintegrating tablet of the present invention can be mixed with a substance to be added as needed according to a conventionally known method for preparing a tablet or a standard method for orally disintegrating an ingot to form an orally disintegrating ingot. According to an embodiment of the present invention, if the active substance of the orally disintegrating tablet has a substance having a bitter taste, astringency or an odor, the pretreatment of the substance with the polymer material may be performed first, and then the above is performed. Oral ingot preparation method.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

Example 1 General Preparation Method and Disintegration Experiment of Oral Disintegration

The active material having a bitter taste, astringency or an odor is pretreated and coated with a liquid polymer material such as glyceride and palm wax or gum arabic. The oil liquid component raw material is first adsorbed by aerosil gum (Aerosil). The raw material of the above-mentioned processing component and the raw material of the poorly soluble component are first pulverized and passed through a sieve of No. 80-120 to have a particle diameter of between 125 μm and 180 μm.

The active substance or component material with high solubility and good taste is mixed with disintegrating agent, flavoring agent, binder and lubricant, and evenly passed through a sieve of No. 60-100 to have a particle diameter of between 150 μm and 250 μm.

All of the above raw material powders are mixed with a diluent and then subjected to tableting, and are carried out at room temperature for about 30 to 60 minutes, and the hardness of the tablet is controlled to be between 3 and 7 kg.

The orally disintegrating ingots of the different formulations listed in the following examples can be prepared as described above. At the same time, the disintegration test is as follows: in the laboratory, a flat tube (capacity 25 mL diameter 1.6 cm) is added to 2 mL of distilled water, and 6 tablets are placed in a test tube to visually observe the collapse state of the mouth collapse, 95%. The above volume collapse was judged as completion of the collapse, and the time was recorded.

Example 2

The purpose of this example is to exemplify the combination of the disintegrating agent and the diluent formulation of the present invention, which can increase the active substance content of the orally disintegrating tablet by as much as 40 to 70% by weight, and the disintegration speed is rapid, as shown in Table 1.

Example 3

The purpose of this example is to illustrate the disintegration effect of using granulated lactose with other diluents (generally lactose). As shown in Table II, the mouth-disintegrated ingots of the A1 group are generally lactose, which has poor disintegration effect and cannot meet the regulations of the regulations; however, if the granulated lactose or granulated mixed lactose is used as a diluent according to the present invention, That is, the formulation of the group A2, A3 and A4 of the mouth-disintegrating group has an active substance content of 21% by weight and can be disintegrated within 60-75 seconds.

Example 4

The purpose of this embodiment is to exemplify the use of granulated lactose or granulated mixed lactose as a diluent in the present invention, which is superior to mannitol which is generally used, and if the disintegrating agent is used together with a foaming agent, the active substance content of the orally disintegrating tablet can be increased. Up to 30% by weight, and the rate of disintegration is very rapid, as shown in Table III.

Example 5

The purpose of this experiment is to exemplify that the orally disintegrating ingot of the present invention can significantly reduce the bitterness after coating the active substance having a marked bitter taste with a polymer material. The polymer coating material used in the experiment was glyceryl dibehenate, the bitter substance was nicotinic amine, and the orally disintegrating ingot was prepared by the preparation method of Example 1. The mouth-breaking ingot was given to each test group (3 persons in each group) for taste test, and the bitterness appearance time was calculated from the time of taking the oral cavity, and the subject score was provided by the tester in a 10-point scale (0 is divided into no bitterness, 10 points) Extremely bitter). The results of each mouth-breaking formula and subject are shown in Table IV.

As can be seen from Table IV, when the bitter substance is coated with the polymer material, the release time of the bitterness is delayed and the discomfort of the user is reduced.

Example 6

The purpose of this experiment is to exemplify that the orally disintegrating ingot of the present invention can significantly reduce the bitterness after coating the active material having a significant bitterness with the coating material. The orally disintegrating tablets of the vitamin B group pre-coated with the uncoated material (No. C3-1 group), and the glyceryl dibehenate (1:1) were prepared by the formulation of the M3 ingot in the C3 group of Example 4. Oral disintegration coated with vitamin B group (No. C3-2 group). The above two kinds of orally disintegrating ingots were respectively administered to five subjects, and the subjects were asked to provide subjective scores on a 10-point scale (0 is not bitter at all, and 10 is extremely bitter). The results of each oral ingot formulation and subject are shown in Table V.

As can be seen from Table V, the bitterness of the orally disintegrated ingot treated with glyceryl dibehenate was clearly covered, and the subject hardly had a bitter taste.

Modifications and modifications are possible in accordance with the embodiments of the present invention without departing from the scope of the invention. It is to be understood that the invention is not to be limited to the scope of the inventions disclosed herein,

Claims (20)

An orally disintegrating tablet characterized by comprising 40% by weight to 80% by weight of active substance, further comprising 2% by weight to 10% by weight of a disintegrating agent; 10% by weight to 75% by weight of a diluent; and containing no stearic acid Magnesium; wherein the disintegrating agent is mixed with 1% by weight to 9% by weight of the foaming agent, and the total amount of the two does not exceed 10% by weight of the total weight of the orally disintegrating ingot; wherein the diluent is 10% by weight to 90% by weight A mixture of % starch and 90% by weight to 10% by weight of a mixture of lactose is granulated to form a mixture of lactose. For example, the oral cavity ingot of the first application of the patent scope, wherein the active substance is a medicine or a nutritional supplement or a substance having health improving effects on the human body. For example, the oral cavity ingot of claim 1 is wherein the active substance is a nutritional supplement. For example, the mouth-disintegrating ingot of the first application of the patent scope, wherein the disintegrating agent is a swelling type disintegrating agent. An orally disintegrating tablet according to claim 1, wherein the disintegrating agent comprises 2% to 6% by weight of a swelling type disintegrating agent, and 2% to 6% by weight of a foaming agent, and both The total amount does not exceed 10% by weight of the total weight of the orally disintegrating ingot. The mouth-disintegrating tablet of claim 4, wherein the swelling-type disintegrating agent is selected from the group consisting of Low-substituted Hydroxypropyl Cellulose and Sodium Carboxymethyl Starch (Sodium) Starch Glycolate (SSG), Crospovidone (PVPP), Hydroxyxy Propion Starch and Cross-linked Sodium Carboxymethyl Cellulose Sodium. An orally disintegrating tablet according to claim 4, wherein the blowing agent is a gas generating type disintegrating agent that produces carbon dioxide or a foam generating surfactant or a combination thereof. For example, the mouth-disintegrating tablet of claim 7 wherein the gas-generating disintegrating agent is a combination of sodium hydrogencarbonate and a group selected from the group consisting of citric acid and apple Acid, tartaric acid, phosphoric acid, lactic acid, gluconic acid, vitamin C, acetic acid and salicylic acid. An orally disintegrating ingot according to claim 7, wherein the surfactant is a combination of one or more selected from the group consisting of vitamin E, sodium laurate, octanoic acid, azone, and lauryl sulfate. Sodium, and polyethylene glycol. An orally disintegrating ingot according to the first aspect of the patent application has a shape such as a circular arc shape, a triangular arc shape, a platelet type, a disk shape or a dome shape. For example, the mouth-disintegrating tablet of claim 1 may further add a flavoring agent, a coloring agent, a fragrance, a lubricant or a binder. The orally disintegrating tablet of claim 11, wherein the total amount of the flavoring agent, coloring agent, perfume, lubricant or binder is from 0.1% by weight to 20% by weight. For example, the mouth-disintegrating ingot of the first aspect of the patent application, wherein the mouth-disintegrating ingot may further be added with a skin-absorbing absorbent. An orally disintegrating tablet according to claim 17, wherein the transdermal absorbent is from 1% by weight to 5% by weight. For example, the mouth-disintegrating ingot of the first application of the patent scope, wherein the mouth-disintegrating ingot may further add an absorption enhancer. An orally disintegrating tablet according to claim 15 wherein the absorption enhancer is from 1% by weight to 5% by weight. For example, the orally disintegrating ingot of the first aspect of the patent application may additionally coat the active substance having a bitterness, astringency or an odor with a coating material. An orally disintegrating tablet according to claim 17, wherein the covering material is a combination of one or more selected from the group consisting of a saccharide, an alkanol, a fatty acid, a phospholipid, a glyceride, a wax, and a plasticization. Agents and gums. An orally disintegrating tablet according to claim 18, wherein the gum substance is selected from the group consisting of cetyl alcohol, Glyceryl Dibehenate, beeswax, sucrose, shellac, gum arabic, and ethyl fiber. And a group consisting of hydroxypropyl methylcellulose. The orally disintegrating tablet of claim 17 wherein the active substance having bitterness, astringency or odor is first coated with a coating material.