WO2008136636A1 - Composition for fast disintegrating tablet containing herbal extract and its preparation method - Google Patents
Composition for fast disintegrating tablet containing herbal extract and its preparation method Download PDFInfo
- Publication number
- WO2008136636A1 WO2008136636A1 PCT/KR2008/002555 KR2008002555W WO2008136636A1 WO 2008136636 A1 WO2008136636 A1 WO 2008136636A1 KR 2008002555 W KR2008002555 W KR 2008002555W WO 2008136636 A1 WO2008136636 A1 WO 2008136636A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formulation
- oligosaccharide
- herbal extract
- starch
- rapidly disintegrating
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 129
- 239000012676 herbal extract Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims description 16
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 12
- 230000000996 additive effect Effects 0.000 claims description 12
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/27—Asclepiadaceae (Milkweed family), e.g. hoya
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Definitions
- the present invention relates to a composition for a formulation rapidly disintegrating in the mouth and a preparation method thereof and, more particularly, to a composition for an oral formulation comprising an herbal extract with improved fast disintegration properties and a method for preparation thereof.
- An oral formulation rapidly disintegrating in the mouth that is, a rapidly disintegrating oral formulation according to the present invention means a formulation that spontaneously dissolves or disintegrates in the mouth, and, thus, is capable of being administered without water.
- a rapidly disintegrating oral formulation which is rapidly dissolving or disintegrating (often referred to as a "rapidly disintegrating formulation") in the mouth, can be easily taken by a patient.
- a rapidly disintegrating formulation capable of being swallowed without water is preferably employed under different circumstances, in particular, that a patient is on a trip, does not have immediate access to water, or has difficulty in swallowing a tablet form of drug. Accordingly, it is expected that the rapidly disintegrating oral formulation will improve patient compliance if applied to manufacture of herbal extract or oriental medicine based formulations.
- Japanese Patent Laid-Open Publication No. H9-48726 proposed a rapidly disintegrating oral formulation including a shape retention material, fabricated by wetting a drug containing granular materials through humidification and compression molding and drying the wetted material to form a shaped product, wherein the shape retention material was exemplified by sugars, sugar alcohols and aqueous polymers.
- Japanese Patent Laid-Open Publication No. H5-271054 disclosed a tablet manufacturing method comprising tablet-pressing a mixture of drugs and sugars with desired water content sufficient to moisturize a surface of sugar particles and drying the treated mixture to produce a tablet.
- Japanese Patent Laid- Open Publication No. H8-291051 described a tablet manufacturing method comprising moisturizing a mixture including a drug, an aqueous binder and an aqueous excipient after tablet-pressing the same at low pressure and drying the wetted mixture to produce a tablet.
- all of the inventions described in the above publications have problems in that the mixture is wetted or moisturized state difficult to treat using any conventional tablet presses and, in addition, moisturizing and drying steps are necessarily conducted after the tableting process thereby causing increase of processing steps.
- compositions used in these methods typically comprise pharmacologically active medical ingredients in an amount of 0.001 to 50% by weight (“wt.%") relative to total weight of the compositions and the balance of other additives such as an excipient, a disintegrating agent and/or a sweetening agent.
- the above methods also have a problem of decreased disintegration speed if applied to manufacture of rapidly disintegrating formulations containing more than 40% active ingredient.
- a single dose of the active ingredient is more than 0.5mg, an amount of the formulation increases to more than Ig which is inconvenient to orally receive or swallow.
- Korean Patent Laid-Open Publication No. 0098009 describes a method for manufacturing a rapidly disintegrating oral tablet which comprises granulating a mixture containing pharmacologically active water- soluble ingredients and an adsorption agent to form a granular substance, preparing a composition containing the granular substance as well as D-mannitol and a disintegrating agent, and compression molding the composition to produce the tablet.
- a ratio of D-mannitol and the disintegrating agent to the formulation ranged from 50 to 99%.
- the rapidly disintegrating formulation substantially becomes 1 to 5Og in a single dose which is too much for a patient to swallow, thereby decreasing patient compliance.
- the above publication suggested that the rapidly disintegrating tablet manufactured using any of the conventional techniques described above preferably had a small size, for example, a table diameter ranging from 6 to 9mm corresponding to a tablet weight ranging from 80 to 250mg.
- the present invention is designed to alleviate bitterness of traditional herbal extracts and, in turn, enhance medical compliance in patients, particularly, pediatric patients.
- the present invention is devised to solve the conventional problems described above and an object of the present invention is to provide a rapidly disintegrating oral formulation easily acceptable even by pediatric or elderly patients, which is fabricated by greatly reducing amount of an excipient to decrease weight of the formulation and, if the active ingredients comprise bitter herbal extracts, improving the taste of the formulation to eliminate patient discomfort during disintegration in the mouth.
- Active ingredients used in the present invention include herbal extracts in liquid or powder form.
- the present invention provides a formulation with improved taste and rapid disintegration in the mouth, which is fabricated by adding a small amount of a disintegrating agent, a binder, a sweetening agent and/or flavors to an active ingredient substantially comprising an herbal extract in a liquid or powder form and lyophilizing the mixture.
- the herbal extract used in the present invention may include water- soluble extracts soluble in water and/or extracts obtained using an organic solvent.
- the present invention uses an herbal extract or dried herbal extract powder.
- the extract is preferably concentrated to a desired concentration before use in order to maximize reduction in volume of a final formulation. More preferably, the herbal extract is dried via spray drying or lyophilization then re-dissolved to achieve a desired concentration effective to more correctly regulate a dose of the extract.
- content of the herbal extract in a dried formulation preferably ranges from 20 to 99.9wt.% and, more preferably, 40 to 99wt.%. If the content is less than 20wt.%, a volume of the entire formulation increases, causing discomfort to patients during oral administration thereof, thereby possibly causing a decrease in patient medical compliance (hereinafter referred to as "patient compliance"). On the other hand, with the content of more than 99.9wt.%, it is difficult to expect desirable effects of other additives.
- a solid content in a water-soluble solution before lyophilization preferably ranges 5 to 60wt.% and, more preferably, 10 to 45wt.%. If the content is less than 5wt.%, a volume of the formulation increases while cohesiveness of the same decreases, resulting in fragile formulation, although the formulation has a short disintegration time. In addition, when the content is more than 60wt.%, a viscosity of the formulation increases, possibly causing trouble during processing and increasing disintegration time.
- a chamber containing a mixture may be maintained at a low temperature for a constant period of time and, at the beginning of drying, the temperature is preferably maintained at -10 ° C or less.
- a time period required for the lyophilization depends on an amount of the mixture to be lyophilized and/or a concentration of the herbal extract. In particular, raising the temperature after maintaining the low temperature for at least 1 hour, the combined mixture is dried.
- One reason for maintaining the low temperature during lyophilization is because the herbal extract is concentrated to induce a sample lyophilized to have a very low melting point due to freezing point depression.
- the mold used in the present invention is not particularly limited but preferably includes a mold with a small height but wider surface areas of top and bottom sides of the mold. This is because a penetration depth of saliva must be shortened in order to decrease disintegration time, and this is achieved when an oral formulation has a greater surface area contacting a tongue portion on which a relatively large amount of saliva is gathered.
- the formulation may further include a variety of additives such as a bitterness masking agent, a sweetening agent, flavors, etc.
- additives may include any commercially available additive approved for human use, for example, at least one selected from a group consisting of polyvinyl pyrrolidol derivatives such as crospovidone, sodium carboxymethylcellulose, sodium starch glycolate, croscarmellose sodium, low- substituted hydroxypropyl cellulose, aspartame, ascorbic acid, citric acid, thaumatin, maltitol, sorbitol, mannitol, erythritol, lactitol, xylitol, reduced (hydrogenated) starch hydrolysates, saccharine, Licorice extract, stevia sweetener, mogrososide, sucrose, isomerized sugar, palatinose, isomalto-oligosaccharide, malto-oligosaccharide, fructo-oligo
- the additives more preferably include at least one selected from a group consisting of crospovidone, sodium carboxymethylcellulose, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, aspartame, ascorbic acid and fruit flavors.
- An amount of the additive contained in a composition for a rapidly disintegrating formulation according to the present invention ranges from 0.001 to 40% by weight ("wt.%") and, more preferably, 0.001 to 20wt.% relative to total weight of the composition. With a content of less than 0.001wt.%, the additive cannot sufficiently improve bitterness of the herbal extract. On the other hand, additional improvement is not expected even when the content exceeds 40wt.%.
- the formulation exhibits excellent rapid disintegration but contains a high concentration of herbal extract. Adding an additive to this formulation, surface blooming and/or surface unevenness may occur in the prepared rapidly disintegrating formulation. In order to remove this defect, a particular additive for improving the surface of the formulation can be contained in the formulation, in addition to use of the lyophilization method.
- Such additive is not particularly limited but preferably includes at least one selected from a group consisting of: polyvinyl pyrrolidol derivatives such as crospovidone, povidone, etc.; starches such as sodium starch glycolate, starch, pregelatinized starch, gelatin, corn starch, tapioca starch, etc.; cellulose and derivatives thereof such as sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropylcellulose, hydroxylpropylcellulose, low-substituted cellulose, microcrystalline cellulose, methylcellulose, etc.; and saccharides such as mannose, sucrose, xylitol, mannitol, trehalose, glucose, maltitol, lactose, fructose, etc.
- polyvinyl pyrrolidol derivatives such as crospovidone, povidone, etc.
- starches such as sodium starch glycolate
- the composition of the present invention includes at least one additive selected from a group consisting of crospovidone, carboxymethylcellulose sodium, croscarmellose sodium, sodium starch glycolate and low-substituted hydroxypropylcellulose.
- An amount of the additive ranges from 0.5 to 60wt.% and, more preferably, 1 to 30wt.% relative to total weight of the composition. Minimal improvement in surface blooming is obtained when the additive amount is less than 0.5wt.%. When the amount exceeds 60wt.%, the entire dose of the formulation is too large to orally administer to a patient thereby possibly reducing patient compliance.
- Mode for invention is
- Preparation Example 2 Preparation of Sopungyangjetang (a medicinal herbal tea) extract powder Main ingredients contained in a wrapper of the herbal tea:
- a composition was prepared. After dissolving or dispersing the prepared composition in water, the solution was poured into a mold and frozen in a lyophilization chamber at -40 ° C . After maintaining the chamber at -40 ° C for 3 hours, the temperature of the chamber was moderately elevated to 40 ° C by 5 ° C per hour to dry the composition in the chamber. The resulting formulation had a thickness of 4mm.
- a formulation was produced by compressing the composition for a rapidly disintegrating formulation according to Example 8 by means of a conventional process.
- a formulation was produced by compressing the composition for a rapidly disintegrating formulation according to Example 10 by means of a conventional process.
- a formulation was produced by compressing the composition for a rapidly disintegrating formulation according to Example 12 by means of a conventional process.
- the rapidly disintegrating formulation of the present invention was subjected to disintegration time measurement.
- each of the specimens was orally administered to five (5) volunteers. More particularly, the sample was placed on the tongue of each person and time taken for the sample to completely disintegrate was measured.
- Example 8 Appearance of the rapidly disintegrating formulation produced in Example 8 was observed and compared to that of the formulation produced in Comparative Example 4.
- the formulation according to the present invention (Example 8) showed favorable surface quality without surface blooming, while the formulation produced using common lyophilization (Comparative Example 4) exhibited surface blooming.
- Example 1 to 36 and Comparative Example 5 each of the samples was orally administered to some volunteers. More particularly, the sample was placed on the tongue of each person and a masking effect of bitterness of the sample was measured. The results are shown in Table 5.
- the degree of bitterness for the formulation applied in the mouth was determined on the following criteria.
- the formulation produced using the composition according to Comparative Example 5 had an unpleasant taste caused by very strong bitterness. Conversely, it was found that the formulations produced using the compositions according to Examples 1 to 36 exhibited excellent bitterness masking effects such that the volunteers were substantially unaware of bitterness of the formulations.
- the present invention provides a rapidly disintegrating formulation for oral administration comprising an herbal extract.
- This formulation can be conveniently and correctly applied to patients who experience difficultly swallowing, such as pediatric and/or elderly patients, via oral administration.
- the formulation of the present invention has additional advantages including, for example, increased carrying convenience and easy dosage, so as to preferably improve patient compliance in drug administration.
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Abstract
Disclosed is a rapidly disintegrating oral formulation comprising a herbal extract. The oral formulation of the present invention can be rapidly dissolved or disintegrated in the mouth and, therefore, easily applied to patients via oral administration. In particular, the formulation is effectively administered to patients with weak swallowing functions such as pediatric and/or elderly patients, patients with mental illnesses and so on. In addition, unlike other general formulations for oral administration, the formulation of the present invention which is simply taken or swallowed without water is useful for patients who are on a trip or do not have immediate access to water. Accordingly, it is expected that the rapidly disintegrating oral formulation of the present invention will improve patient compliance if applied to manufacture of herbal extract or oriental medicine based formulations.
Description
COMPOSITION FOR FAST DISINTEGRATING TABLET CONTAINING HERBAL EXTRACT AND ITS PREPARATION METHOD
Technical Field
The present invention relates to a composition for a formulation rapidly disintegrating in the mouth and a preparation method thereof and, more particularly, to a composition for an oral formulation comprising an herbal extract with improved fast disintegration properties and a method for preparation thereof. An oral formulation rapidly disintegrating in the mouth, that is, a rapidly disintegrating oral formulation according to the present invention means a formulation that spontaneously dissolves or disintegrates in the mouth, and, thus, is capable of being administered without water.
Background Art
It is known that some patients suffer from difficulty in swallowing tablets or capsules and even about 20% of patients reject formulations administered in tablet form. However, a rapidly disintegrating oral formulation, which is rapidly dissolving or disintegrating (often referred to as a "rapidly disintegrating formulation") in the mouth, can be easily taken by a patient. Especially, such formulations can be efficiently applied to patients who experience difficulty swallowing, for example, pediatric and/or elderly patients, patients with mental illnesses (psychiatric patients) and so on. Unlike other general formulations for oral administration, the rapidly disintegrating formulation capable of being swallowed without water is preferably employed under different circumstances, in particular, that a patient is on a trip, does not have immediate access to water, or has difficulty in swallowing a tablet form of drug. Accordingly, it is expected that the rapidly disintegrating oral formulation will improve patient compliance if applied to manufacture of herbal extract or oriental medicine based formulations.
A number of conventional techniques or methods for manufacturing formulations for oral administration capable of being rapidly dissolved and/or disintegrated in the mouth have been disclosed. For example, Japanese Patent Laid-Open Publication No. H9-48726 proposed a rapidly disintegrating oral formulation including a shape retention material, fabricated by wetting a drug
containing granular materials through humidification and compression molding and drying the wetted material to form a shaped product, wherein the shape retention material was exemplified by sugars, sugar alcohols and aqueous polymers. Japanese Patent Laid-Open Publication No. H5-271054 disclosed a tablet manufacturing method comprising tablet-pressing a mixture of drugs and sugars with desired water content sufficient to moisturize a surface of sugar particles and drying the treated mixture to produce a tablet. Japanese Patent Laid- Open Publication No. H8-291051 described a tablet manufacturing method comprising moisturizing a mixture including a drug, an aqueous binder and an aqueous excipient after tablet-pressing the same at low pressure and drying the wetted mixture to produce a tablet. However, all of the inventions described in the above publications have problems in that the mixture is wetted or moisturized state difficult to treat using any conventional tablet presses and, in addition, moisturizing and drying steps are necessarily conducted after the tableting process thereby causing increase of processing steps.
Other techniques have also been proposed, including, for example, a method for production of a drug formulation that comprises dissolving or suspending medical ingredients in an aqueous solvent, filling a preformed mold such as a blister pack with the solution or suspension, and lyophilizing the solution or suspension (as disclosed in US Patent Nos. 4371516 and 4946684) or vacuum drying the solution (as disclosed in US Patent No. 5466464) so as to remove water from the solution. Most compositions used in these methods typically comprise pharmacologically active medical ingredients in an amount of 0.001 to 50% by weight ("wt.%") relative to total weight of the compositions and the balance of other additives such as an excipient, a disintegrating agent and/or a sweetening agent. However, the above methods also have a problem of decreased disintegration speed if applied to manufacture of rapidly disintegrating formulations containing more than 40% active ingredient. In addition, if a single dose of the active ingredient is more than 0.5mg, an amount of the formulation increases to more than Ig which is inconvenient to orally receive or swallow.
Furthermore, Korean Patent Laid-Open Publication No. 0098009 describes a method for manufacturing a rapidly disintegrating oral tablet which comprises granulating a mixture containing pharmacologically active water- soluble ingredients and an adsorption agent to form a granular substance,
preparing a composition containing the granular substance as well as D-mannitol and a disintegrating agent, and compression molding the composition to produce the tablet. For the tablet manufactured using the above composition and applied to manufacture a rapidly disintegrating formulation, a ratio of D-mannitol and the disintegrating agent to the formulation ranged from 50 to 99%. Accordingly, when a single dose of the pharmacologically active ingredients is about 0.5g dry weight, the rapidly disintegrating formulation substantially becomes 1 to 5Og in a single dose which is too much for a patient to swallow, thereby decreasing patient compliance. In particular, the above publication suggested that the rapidly disintegrating tablet manufactured using any of the conventional techniques described above preferably had a small size, for example, a table diameter ranging from 6 to 9mm corresponding to a tablet weight ranging from 80 to 250mg.
Disclosure of Invention
Technical Problem
As a result of extensive studies in regard to reduction of content of an excipient other than active ingredients and simplification of a process for preparation of a tablet formulation thereby improving patient compliance, the inventors found a solution to minimize weight of the formulation, which has never been proposed among conventional methods in the related art. The present invention is designed to alleviate bitterness of traditional herbal extracts and, in turn, enhance medical compliance in patients, particularly, pediatric patients. Accordingly, the present invention is devised to solve the conventional problems described above and an object of the present invention is to provide a rapidly disintegrating oral formulation easily acceptable even by pediatric or elderly patients, which is fabricated by greatly reducing amount of an excipient to decrease weight of the formulation and, if the active ingredients comprise bitter herbal extracts, improving the taste of the formulation to eliminate patient discomfort during disintegration in the mouth.
Technical Solution
Active ingredients used in the present invention include herbal extracts in liquid or powder form. The present invention provides a formulation with improved taste and rapid disintegration in the mouth, which is fabricated by adding a small amount of a disintegrating agent, a binder, a sweetening agent and/or flavors to an active ingredient substantially comprising an herbal extract in a liquid or powder form and lyophilizing the mixture.
The herbal extract used in the present invention may include water- soluble extracts soluble in water and/or extracts obtained using an organic solvent.
Best Mode
Hereinafter, the present invention will be described in more detail.
The present invention uses an herbal extract or dried herbal extract powder. When using the herbal extract, the extract is preferably concentrated to a desired concentration before use in order to maximize reduction in volume of a final formulation. More preferably, the herbal extract is dried via spray drying or lyophilization then re-dissolved to achieve a desired concentration effective to more correctly regulate a dose of the extract. In this regard, content of the herbal extract in a dried formulation preferably ranges from 20 to 99.9wt.% and, more preferably, 40 to 99wt.%. If the content is less than 20wt.%, a volume of the entire formulation increases, causing discomfort to patients during oral administration thereof, thereby possibly causing a decrease in patient medical compliance (hereinafter referred to as "patient compliance"). On the other hand, with the content of more than 99.9wt.%, it is difficult to expect desirable effects of other additives.
A solid content in a water-soluble solution before lyophilization preferably ranges 5 to 60wt.% and, more preferably, 10 to 45wt.%. If the content is less than 5wt.%, a volume of the formulation increases while cohesiveness of the same decreases, resulting in fragile formulation, although the formulation has a short disintegration time. In addition, when the content is more than 60wt.%, a viscosity of the formulation increases, possibly causing trouble during processing and increasing disintegration time.
During the lyophilization, a chamber containing a mixture may be maintained at a low temperature for a constant period of time and, at the
beginning of drying, the temperature is preferably maintained at -10 °C or less. A time period required for the lyophilization depends on an amount of the mixture to be lyophilized and/or a concentration of the herbal extract. In particular, raising the temperature after maintaining the low temperature for at least 1 hour, the combined mixture is dried. One reason for maintaining the low temperature during lyophilization is because the herbal extract is concentrated to induce a sample lyophilized to have a very low melting point due to freezing point depression. However, even an aqueous solution with high concentration exhibits melting point elevation according to the Clapeyron Equation when a pressure of the solution decreases under vacuum, thereby maintaining the lyophilized condition. Consequently, although a surface of the lyophilized sample does not melt during lyophilization, the vacuum pressure effect is not transferred to the internal portion of the sample at the beginning of lyophilization so that the inside of the sample becomes liquefied before completing lyophilization, thus causing a surface blooming defect. As a result, the formulation cannot maintain an original form as lyophilized in a mold.
The mold used in the present invention is not particularly limited but preferably includes a mold with a small height but wider surface areas of top and bottom sides of the mold. This is because a penetration depth of saliva must be shortened in order to decrease disintegration time, and this is achieved when an oral formulation has a greater surface area contacting a tongue portion on which a relatively large amount of saliva is gathered.
In order to improve formulation taste, the formulation may further include a variety of additives such as a bitterness masking agent, a sweetening agent, flavors, etc. Such additives may include any commercially available additive approved for human use, for example, at least one selected from a group consisting of polyvinyl pyrrolidol derivatives such as crospovidone, sodium carboxymethylcellulose, sodium starch glycolate, croscarmellose sodium, low- substituted hydroxypropyl cellulose, aspartame, ascorbic acid, citric acid, thaumatin, maltitol, sorbitol, mannitol, erythritol, lactitol, xylitol, reduced (hydrogenated) starch hydrolysates, saccharine, Licorice extract, stevia sweetener, mogrososide, sucrose, isomerized sugar, palatinose, isomalto-oligosaccharide, malto-oligosaccharide, fructo-oligosaccharide, soybean oligosaccharide, fructose, lactose, maltose, glucose, xylose, isomerized lactose, galacto-oligosaccharide, xylo-oligosaccharide, dextrose syrup and fruit flavors. The additives more
preferably include at least one selected from a group consisting of crospovidone, sodium carboxymethylcellulose, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, aspartame, ascorbic acid and fruit flavors. An amount of the additive contained in a composition for a rapidly disintegrating formulation according to the present invention ranges from 0.001 to 40% by weight ("wt.%") and, more preferably, 0.001 to 20wt.% relative to total weight of the composition. With a content of less than 0.001wt.%, the additive cannot sufficiently improve bitterness of the herbal extract. On the other hand, additional improvement is not expected even when the content exceeds 40wt.%. For a rapidly disintegrating formulation formed using a lyophilization method, the formulation exhibits excellent rapid disintegration but contains a high concentration of herbal extract. Adding an additive to this formulation, surface blooming and/or surface unevenness may occur in the prepared rapidly disintegrating formulation. In order to remove this defect, a particular additive for improving the surface of the formulation can be contained in the formulation, in addition to use of the lyophilization method. Such additive is not particularly limited but preferably includes at least one selected from a group consisting of: polyvinyl pyrrolidol derivatives such as crospovidone, povidone, etc.; starches such as sodium starch glycolate, starch, pregelatinized starch, gelatin, corn starch, tapioca starch, etc.; cellulose and derivatives thereof such as sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, croscarmellose sodium, low-substituted hydroxypropylcellulose, hydroxylpropylcellulose, low-substituted cellulose, microcrystalline cellulose, methylcellulose, etc.; and saccharides such as mannose, sucrose, xylitol, mannitol, trehalose, glucose, maltitol, lactose, fructose, etc. More preferably, the composition of the present invention includes at least one additive selected from a group consisting of crospovidone, carboxymethylcellulose sodium, croscarmellose sodium, sodium starch glycolate and low-substituted hydroxypropylcellulose. An amount of the additive ranges from 0.5 to 60wt.% and, more preferably, 1 to 30wt.% relative to total weight of the composition. Minimal improvement in surface blooming is obtained when the additive amount is less than 0.5wt.%. When the amount exceeds 60wt.%, the entire dose of the formulation is too large to orally administer to a patient thereby possibly reducing patient compliance.
Mode for invention
Hereinafter, the present invention will become apparent from the following detailed description of preferred embodiments and examples, which are proposed for illustrative purposes only and are not intended to restrict the spirit and scope of the invention.
Examples
[Preparation of herbal extracts] Preparation Example 1 : Preparation of Hyeonggaeyeongyotang (an herbal tea containing Nepetae Herba aqua and Forsythia Fructus, referred to as "herbal tea") extract powder
Main ingredients contained in a wrapper (dose) of the herbal tea:
- Saposhnikoviae Radix and Lonicerae Flos; 8g per each, - Angelicae Gigantis Radix, Cnidii Rhizoma and Paeoniae Radix; 5g per each,
- Nepetae Herba aqua, Forsythia Fructus, Bupleuri Radix, Aurantii Fructus, Scutellaiae Radix, Gardeniae Fructus, Dahuricae Radix, Platycodi Radix, Ulmi cortex, Akebiae caulis and Retinervus luffae Fructus; 4g per each, and - Glycyrrhizae Radix; 2g.
Extraction procedure:
1 pack (comprising 20 wrappers, 1 wrapper=77g), that is, 154Og of the herbal tea was placed in a clay pot for preparing medicine and 6L of water was added thereto. After boiling the mixture for 3 hours, the resulting concentrate was lyophilized by a conventional method. Yield: 20.048% (lyophilized weight as a percentage of the total weight of the original herbal tea).
Preparation Example 2: Preparation of Sopungyangjetang (a medicinal herbal tea) extract powder Main ingredients contained in a wrapper of the herbal tea:
- Angelicae gigantis Radix, Moutan Cortex Radicis and Rehmanniae Radix; 12g per each,
- Glycyrrhizae Radix, Lonicerae Flos, Saposhnikoviae Radix, Spirodela polyrhiza schleider, Forsythia Fructus, Paeonia Radix, Cnidii Rhizoma, Nepetae Herba aqua and Bombycis Corpus; 4g per each, and
- Menthae Herba, Rhinoceri Cornu and Scutellariae Radix; 2g per each. Extraction procedure:
1 pack (comprising 20 wrappers, 1 wrapper=72g), that is, 156Og of the herbal tea was placed in a clay pot for preparing medicine and 6L of water was added thereto. After boiling the mixture for 3 hours, the resulting concentrate was lyophilized by a conventional method. Yield: 14.91% (lyophilized weight as a percentage of the total weight of the original herbal tea).
Preparation Example 3: Preparation of Sopungsan (a medicinal herbal tea) extract powder
Main ingredients contained in a wrapper of the herbal tea:
- Spirodela polyrhiza schleider; 12g per each, and
- Glycyrrhizae Radix, Sophorae Radix, Angelicae gigantis Radix, Cannabis Fructus, Akebiae Caulis, Saposhnikoviae Radix, Rehmanniae Radix, Gypsum Fibrosum, Cryptotympana atrata, Forsythia Fructus, Arctium lappa linne, Atractylodes Rhizoma, Nepetae Herba aqua and Sesamum indicum linne; 4g per each.
Extraction procedure:
1 pack (comprising 20 wrappers, 1 wrapper=68g), that is, 136Og of the herbal tea was placed in a clay pot for preparing medicine and 6L of water was added thereto. After boiling the mixture for 3 hours, the resulting concentrate was lyophilized by a conventional method. Yield: 12.58% (lyophilized weight as a percentage of the total weight of the original herbal tea).
Examples 1 to 36
The formulations according to Examples 1 to 36 were produced by the following procedure:
Admixing particular herbal extract powders and additives listed in Tables 1 to 3 together in a certain ratio, a composition was prepared. After dissolving or dispersing the prepared composition in water, the solution was poured into a mold and frozen in a lyophilization chamber at -40 °C . After maintaining the chamber at -40 °C for 3 hours, the temperature of the chamber was moderately elevated to 40 °C by 5 °C per hour to dry the composition in the chamber. The resulting formulation had a thickness of 4mm.
Table 1
Comparative Example 1
A formulation was produced by compressing the composition for a rapidly disintegrating formulation according to Example 8 by means of a conventional process.
Comparative Example 2
A formulation was produced by compressing the composition for a rapidly disintegrating formulation according to Example 10 by means of a conventional process.
Comparative Example 3
A formulation was produced by compressing the composition for a rapidly disintegrating formulation according to Example 12 by means of a conventional process.
Comparative Example 4
After dissolving 6g of the herbal tea extract powder prepared by Preparation Example 1 in 15g of water, the solution was poured into a mold and frozen in a lyophilization chamber at -70 °C , followed by lyophilization at room temperature according to a conventional method.
Comparative Example 5
After dissolving 6g of the herbal tea extract powder prepared by Preparation Example 1 in 15g of water, the solution was poured into a mold and frozen in a lyophilization chamber at -40 °C . After maintaining the chamber at -
40 °C for 3 hours, the temperature of the chamber was moderately elevated to
40 °C by 5 °C per hour to dry the composition in the chamber. The resulting
formulation had a thickness of 4mm.
Experimental Example 1 : Measurement of disintegration time of the rapidly disintegrating formulation according to the present invention
The rapidly disintegrating formulation of the present invention was subjected to disintegration time measurement.
After preparing test samples of the formulations produced according to Examples 1 to 36 and Comparative Examples 1 to 3, each of the specimens was orally administered to five (5) volunteers. More particularly, the sample was placed on the tongue of each person and time taken for the sample to completely disintegrate was measured.
Table 4
As shown in Table 4, it was found that, if a rapidly disintegrating formulation of the present invention is produced by the preparation method of the
present invention, all compositions used for production of the formulation exhibit reduced disintegration time (see Examples 1 to 36). Whereas, when the formulations were produced by other methods (see Comparative Examples 1 to 3), the disintegration time was considerably extended even with the same composition.
Experimental Example 2: Appearance comparison of rapidly disintegrating formulations
Appearance of the rapidly disintegrating formulation produced in Example 8 was observed and compared to that of the formulation produced in Comparative Example 4. The formulation according to the present invention (Example 8) showed favorable surface quality without surface blooming, while the formulation produced using common lyophilization (Comparative Example 4) exhibited surface blooming.
Experimental Example 3: Determination of bitterness masking effect of the rapidly disintegrating formulation according to the present invention
In order to determine bitterness masking effects of rapidly disintegrating formulations produced as described above, the following experiments were performed:
After preparing test samples of the formulations produced according to
Examples 1 to 36 and Comparative Example 5, each of the samples was orally administered to some volunteers. More particularly, the sample was placed on the tongue of each person and a masking effect of bitterness of the sample was measured. The results are shown in Table 5.
Table 5
1^ The degree of bitterness for the formulation applied in the mouth was determined on the following criteria.
1 : no bitterness 2: slight bitterness
3 : strong bitter taste 4: unpleasant taste caused by very strong bitterness
As shown in Table 5, the formulation produced using the composition according to Comparative Example 5 had an unpleasant taste caused by very strong bitterness. Conversely, it was found that the formulations produced using the compositions according to Examples 1 to 36 exhibited excellent bitterness masking effects such that the volunteers were substantially unaware of bitterness of the formulations.
Industrial Applicability
The present invention provides a rapidly disintegrating formulation for oral administration comprising an herbal extract. This formulation can be conveniently and correctly applied to patients who experience difficultly swallowing, such as pediatric and/or elderly patients, via oral administration.
Alternatively, the formulation of the present invention has additional advantages
including, for example, increased carrying convenience and easy dosage, so as to preferably improve patient compliance in drug administration.
Claims
1. A rapidly disintegrating oral formulation comprising 40 to 99wt.% of at least one herbal extract as an active ingredient, prepared by lyophilization.
2. The formulation according to claim 1, further comprising at least one additive selected from a group consisting of crospovidone, sodium carboxymethylcellulose, sodium starch glycolate, croscarmellose sodium, low- substituted hydroxypropylcellulose, aspartame, ascorbic acid, citric acid, thaumatin, maltitol, sorbitol, mannitol, erythritol, lactitol, xylitol, reduced (hydrogenated) starch hydrolysates, saccharine, Licorice extract, stevia sweetener, mogrososide, sucrose, isomerized sugar, palatinose, isomalto-oligosaccharide, fructo-oligosaccharide, soybean oligosaccharide, fructose, lactose, maltose, glucose, galacto-oligosaccharide, malto-oligosaccharide, xylo-oligosaccharide, dextrose syrup, xylose, isomerized lactose, and fruit flavors, in an amount ranging from 0.001 to 20wt.% relative to total weight of the formulation, for masking bitterness.
3. The formulation according to claim 1 or 2, further comprising at least one additive selected from a group consisting of crospovidone, povidone, sodium starch glycolate, starch, pregelatinized starch, gelatin, corn starch, tapioca starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, croscarmellose sodium, methylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, low-substituted cellulose, microcrystalline cellulose, methylcellulose, cellulose, mannose, sucrose, xylitol, mannitol, trehalose, glucose, maltitol, lactose and fructose, in an amount ranging from 1 to 30wt.% relative to total weight of the formulation, for improving surface quality of the formulation.
4. The formulation according to any one of claims 1 to 3, wherein the herbal extract is an extract obtained by using water or an organic solvent, or a typical herbal formulation for an oriental medicine.
5. A method for preparation of a rapidly disintegrating oral formulation comprising an herbal extract, which includes: mixing an additive with herbal extract powder; dispersing or dissolving the mixture in an aqueous solution; pouring the mixture into a mold and lyophilizing the mixture in a lyophilization chamber at a temperature ranging from -80 to -10°C ; maintaining the chamber at a temperature ranging from -50 to -10 °C for
10 hours; and moderately elevating the temperature to dry the lyophilized product.
6. The method according to claim 5, wherein a solid content of the formulation in the aqueous solution ranges from 10 to 45wt.% before lyophilization.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2007-0044677 | 2007-05-08 | ||
| KR1020070044677A KR100895942B1 (en) | 2007-05-08 | 2007-05-08 | Oral disintegrating preparation composition containing oral herbal extract and method for preparing same |
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| Publication Number | Publication Date |
|---|---|
| WO2008136636A1 true WO2008136636A1 (en) | 2008-11-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2008/002555 WO2008136636A1 (en) | 2007-05-08 | 2008-05-07 | Composition for fast disintegrating tablet containing herbal extract and its preparation method |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR100895942B1 (en) |
| WO (1) | WO2008136636A1 (en) |
Cited By (3)
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| WO2011160849A1 (en) * | 2010-06-24 | 2011-12-29 | Pharmatech Gmbh | Taste-masked pharmaceutical formulation having accelerated onset of action |
| US10143706B2 (en) | 2016-06-29 | 2018-12-04 | Cannscience Innovations, Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
| CN113498860A (en) * | 2021-06-28 | 2021-10-15 | 武汉轻工大学 | Abelmoschus manihot freeze-dried orally disintegrating tablet and preparation method thereof |
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| KR101144613B1 (en) * | 2009-11-06 | 2012-05-11 | 충남대학교산학협력단 | Pharmaceutical composition containing orally disintegrating tablet of chinese medicine BHT for stroke and preparing method thereof |
| KR101599645B1 (en) * | 2014-12-22 | 2016-03-04 | 한국참생약영농조합법인 | Fast disintegrating tablet using powder of pleuropterus multiflorus and red ginseng |
| KR20220071957A (en) * | 2020-11-24 | 2022-05-31 | 에스케이케미칼 주식회사 | Pharmaceutical composition comprising high amount of an active ingredient derived from herbal substances |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011160849A1 (en) * | 2010-06-24 | 2011-12-29 | Pharmatech Gmbh | Taste-masked pharmaceutical formulation having accelerated onset of action |
| EA031697B1 (en) * | 2010-06-24 | 2019-02-28 | Фарматек Гмбх | Taste-masked pharmaceutical formulation having accelerated onset of action |
| US10143706B2 (en) | 2016-06-29 | 2018-12-04 | Cannscience Innovations, Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
| US10383892B2 (en) | 2016-06-29 | 2019-08-20 | CannScience Innovations Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
| US10537592B2 (en) | 2016-06-29 | 2020-01-21 | CannScience Innovations Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
| CN113498860A (en) * | 2021-06-28 | 2021-10-15 | 武汉轻工大学 | Abelmoschus manihot freeze-dried orally disintegrating tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20080099058A (en) | 2008-11-12 |
| KR100895942B1 (en) | 2009-05-07 |
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