CN103619339A - Tablet containing limaprost and ss-cyclodextrin - Google Patents
Tablet containing limaprost and ss-cyclodextrin Download PDFInfo
- Publication number
- CN103619339A CN103619339A CN201280027255.6A CN201280027255A CN103619339A CN 103619339 A CN103619339 A CN 103619339A CN 201280027255 A CN201280027255 A CN 201280027255A CN 103619339 A CN103619339 A CN 103619339A
- Authority
- CN
- China
- Prior art keywords
- tablet
- beta
- limaprost
- schardinger dextrin
- quality
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
Provided is a tablet containing limaprost and ss-cyclodextrin, the ratio of ss-cyclodextrin contained therein being 30-99 mass% with respect to 100 mass% of the tablet as a whole.
Description
Technical field
The present invention relates to the tablet that contains limaprost and beta-schardinger dextrin-.
Background technology
Limaprost is known as the agent that prevents and/or treats of peripheral circulation disorders,, for the improvement of the symptom of chronic disease Buerger's disease, lumbar spinal stenosis etc., is particularly very effective medicine.
Limaprost has hygroscopicity, easily absorbs moisture and decomposes.Therefore, commercially available limaprost alfadex tablet packs in aluminum bag on the basis of PTP packing, to avoid the impact of humidity.
As the stable tablet that contains limaprost, report has: for example, (1) dried frozen aquatic products that contains limaprost alfadex (the alpha-cyclodextrin inclusion body of limaprost) and glucan, and the combination of oral medication of tack is stablized and reduced in (2), it contains: excipient, further optionally contain glucan, pharmaceutical composition is made as to 100 quality %, the containing ratio of glucan is 1～15 quality %, and water activity value is (to refer to Patent Document 1) below 0.2 at 25 ℃.
On the other hand, cyclodextrin generally for to the solubilising of compound, cover the objects such as bitterness or stabilisation and use.For example, known cyclodextrin being dissolved in together with principal agent in aqueous solution, makes principal agent stabilisation by enclose principal agent.Yet, by the enclose of cyclodextrin, may not necessarily can obtain stabilization effect.For example, limaprost alfadex is the compound that utilizes alpha-cyclodextrin that limaprost enclose is formed, even if but limaprost crystallization and alpha-cyclodextrin enclose can not suppressed to limaprost decomposition significantly yet.In addition, when with cyclodextrin inclusion compound principal agent, common known following four methods: emulsion process (for example, in 20～50% suspensions of cyclodextrin, add a certain amount of principal agent, with homogenizer, make its emulsifying), saturated water solution method (for example, principal agent is uniformly mixed to 30 minutes～a couple of days in the saturated aqueous solution of cyclodextrin, after taking out precipitate, the clathrate evaporation water that precipitation is obtained or reduction temperature be dried), mixing method (for example, in cyclodextrin, add a small amount of water to make pasty state, add principal agent fully mixing with mixing roll, based on conventional method, the thickener obtaining is dried), and co-grinding method (for example, will cyclodextrin and principal agent drop in vibromill, pulverize and obtain) (non-patent literature 1), but cyclodextrin is not being dissolved together with principal agent, and while only carrying out simple mixing in the situation that not there is not solvent, can not expect the enclose of principal agent, therefore cannot improve stability by the enclose of principal agent.
For example, report has: by beta-schardinger dextrin-is engaged in, improve stability (patent documentation 2) in pravastatin.In this patent documentation, comprise following operation: by co-grinding, beta-schardinger dextrin-and pravastatin are applied the power of physical property, then, mixing so that beta-cyclodextrin inclusion compound pravastatin with solution.
In addition, known to improve disintegrative, using cyclodextrin as additive for the manufacture of oral cavity quickly disintegrating tablet.About using cyclodextrin as the tablet of additive, for example, report has oral cavity quickly disintegrating tablet, it is characterized in that, 70 quality % in tablet are cyclodextrin (referring to Patent Document 3) above.In cyclodextrin in this patent documentation, also contain beta-schardinger dextrin-.But, do not record or be taught as improve principal agent stability and by cyclodextrin as additive.
Prior art document
Patent documentation
Patent documentation 1: No. 3646310 communique of Japan Patent
Patent documentation 2: Japanese Unexamined Patent Application Publication 2003-517432 communique
Patent documentation 3:WO2005/004923 pamphlet
Non-patent literature
His Vol.210 of non-patent literature 1:Foods & Food Ingredients Journal of Japan (FFI magazine) food food additives research will temple tail, little west, No.3,222-243,2005
Summary of the invention
The problem that invention will solve
On-the-spot in medical treatment, in order to improve patient's convenience (preventing mistake drink, misuse etc.), mostly use polyethylene laminated cellophane etc. by various preparations one packetize of a dose etc.Therefore need such preparation: though from PTP packing is taken out without under packed state, at least in a couple of days to 30 day or within about one month, keep stable.Therefore, require further to improve the stability of the tablet that contains limaprost.
That is, the object of the invention is to: the tablet that contain limaprost highly stable with respect to humidity is provided.Particularly, its object is to provide: preserve 30 days or one month under the condition of 30 ℃ of temperature, relative humidity 75% after, the production rate of catabolite is tablet below 5%, that contain limaprost.
The method of dealing with problems
The inventor etc. are in order to find the tablet that contain limaprost more more stable than the existing tablet that contains limaprost, carried out research with keen determination, found that: in multiple additives, coordinate especially in the situation of beta-schardinger dextrin-, can improve the stability of limaprost.Also find: if only add beta-schardinger dextrin-as additive and limaprost be not dissolved in together with beta-schardinger dextrin-in solvent, limaprost significantly improves with respect to the stability of humidity.This discovery is thrilling, and from existing opinion, although think and be not limited to theory, if only simple mixing limaprost and beta-schardinger dextrin-under the condition that does not have solvent, beta-schardinger dextrin-can enclose limaprost.In addition, sometimes limaprost also as using with the limaprost alfadex that alpha-cyclodextrin has carried out enclose.If but utilize the so existing opinion of enclose of cyclodextrin etc. in view of the stabilisation of limaprost results from, even if those skilled in the art are also difficult to expect improve the such opinion of stabilisation to further adding cyclodextrin with the compound of cyclodextrin inclusion compound.Further find: compare with the existing tablet that contains limaprost, the tablet that contains limaprost and beta-schardinger dextrin-significantly improves with respect to the stability of humidity, thereby has completed the present invention.
That is, the present invention relates to:
1. tablet, it contains limaprost and beta-schardinger dextrin-,
Wherein, using tablet integral body as 100 quality %, contain the beta-schardinger dextrin-of 30～99 quality %.
2. according to the tablet described in 1, wherein, using tablet integral body as 100 quality %, contain the beta-schardinger dextrin-of 50～95 quality %.
3. according to the tablet described in any one in 1～2, it optionally further contains the glucan of 0.0165～2.5 quality %.
4. according to the tablet described in any one in 1～3, wherein, limaprost is contained in described tablet with the form of limaprost alfadex, at this this tablet, at least contains:
(1) mixture of the lyophilizing body that comprises limaprost alfadex and (2) beta-schardinger dextrin-.
5. according to the tablet described in 4, it is manufactured by comprising following operation:
Under the condition that does not have solvent, mix the operation of adding (2) beta-schardinger dextrin-.
6. according to the tablet described in 5, wherein, in lyophilizing body, further contain beta-schardinger dextrin-.
7. according to the tablet described in 6, wherein, using tablet integral body as 100 quality %, the beta-schardinger dextrin-in lyophilizing body is 0.1～1 quality %.
8. according to the tablet described in any one in 4～7, wherein, in lyophilizing body, further contain glucan.
9. according to the tablet described in 8, wherein, with the ratio of 1:0.1～15, contain limaprost alfadex and glucan.
10. according to the tablet described in 8, wherein, with the ratio of 1:0.1～6, contain limaprost alfadex and glucan.
11. tablets, it contains limaprost alfadex, beta-schardinger dextrin-and glucan,
Wherein, using tablet integral body as 100 quality %, contain the beta-schardinger dextrin-of 30～99 quality %, the glucan of 0.0165～2.5 quality %.
12. tablets, it contains: the mixture of the lyophilizing body that (1) comprises limaprost alfadex, beta-schardinger dextrin-and glucan and (2) beta-schardinger dextrin-,
Wherein, using tablet integral body as 100 quality %, contain the beta-schardinger dextrin-of 30～99 quality %, the glucan of 0.0165～1.0 quality %.
13. according to the tablet described in any one in 1～12, wherein, under the condition of 30 ℃ of temperature, relative humidity 75%, preserves after one month, does not contain in fact 17S, 20-dimethyl-trans-Δ in tablet
2-PGA
1, or using tablet integral body as 100%, 17S, 20-dimethyl-trans-Δ
2-PGA
1be below 5%.
limaprost
In this manual, limaprost is the compound shown in following formula (I),
[Chemical formula 1]
Chemistry (E)-7-[(1R by name, 2R, 3R)-3-hydroxyl-2-[(3S, 5S)-(E)-3-hydroxy-5-methyl base-1-nonene base]-5-oxocyclopentyl]-2-enanthic acid (accession number 74397-12-9).
In addition, in this manual, limaprost also can comprise the form of having carried out enclose with alpha-cyclodextrin.The alpha-cyclodextrin clathrate of limaprost is the compound shown in following formula (II),
[Chemical formula 2]
(in formula, n represents integer)
Generic name is (E)-7-[(1R, 2R, 3R)-3-hydroxyl-2-[(3S, 5S)-(E)-3-hydroxy-5-methyl base-1-nonene base]-5-oxocyclopentyl]-2-enanthic acid alpha-cyclodextrin clathrate (accession number 100459-01-6 (limaprost: alpha-cyclodextrin=1:1), 88852-12-4 (limaprost: alpha-cyclodextrin=1:n)), is generally known as limaprost alfadex.Its with record " limaprost alfadex " synonym in the 16 revised edition Japanese Pharmacopoeia.
In the present invention, unless otherwise noted, as those skilled in the art institute clearly, symbol
[chemical formula 3]
Represent to be bonded in the rear side (being α-configuration) of paper,
[chemical formula 4]
Represent to be bonded in the front face side (being beta comfiguration) of paper.
In the present invention, preferably with the alpha-cyclodextrin clathrate of the limaprost shown in above-mentioned formula (II), be that the form of limaprost alfadex contains limaprost.
In a preferred embodiment, the limaprost that contains 5～10 μ g that have an appointment in a slice tablet of the present invention.In addition, in the situation that contain limaprost with the form of limaprost alfadex, be converted into limaprost, also preferably in a slice, contain 5～10 μ g that have an appointment.
Limaprost and limaprost alfadex are known, can, by known method, such as method of recording in Japanese kokai publication sho 55-100360 etc., manufacture.
If limaprost decomposes, as catabolite, generate the 17S shown in following formula, 20-dimethyl-trans-Δ
2-PGA
1(below referred to as 11-deoxidant body),
[chemical formula 5]
Or the 17S shown in following formula, 20-dimethyl-trans-Δ
2the iso-PGE of-8-
1(below referred to as 8-isomer), etc.
[chemical formula 6]
Known as catabolite, generate be mainly 11-deoxidant body.If the growing amount of these catabolites increases, worry that drug effect weakens.The medicament that contains limaprost of the present invention is highly stable, even therefore in the on-the-spot long preservation of medical treatment, also the growing amount of 11-deoxidant body can be suppressed at more than detectability approximately below 10%, preferably be suppressed at more than detectability approximately below 8%, be further preferably suppressed at more than detectability approximately below 5%.In addition, even in the humidification carrying out and the test of the preservation under heating condition in order to predict the storage stability that medical treatment is on-the-spot, the growing amount that also can suppress 11-deoxidant body makes it lower.Particularly, the growing amount of preserving the 11-deoxidant body after 30 days or month at 30 ℃ of temperature for example, relative humidity for 75% time preferably can be suppressed at more than detectability approximately below 5%, be further preferably suppressed at more than detectability approximately below 3.5%.In addition, the growing amount of preserving the 11-deoxidant body after 30 days or month at temperature 60 C preferably can be suppressed at more than detectability approximately below 5%, be further preferably suppressed at detectability above approximately below 3.5%.
The production rate of 11-deoxidant body for example can the ratio (mass ratio) with respect to the total amount of limaprost and 11-deoxidant body, 8-isomer represent by the amount of the 11-deoxidant body in compositions.
The production rate of 11-deoxidant body can be by the catabolite of limaprost and limaprost (8-isomer, 11-deoxidant body) is carried out quantitatively, by limaprost and catabolite and be made as 100 and calculate.
The amount of limaprost and 11-deoxidant body, 8-isomer can be measured by known analytical method (such as high performance liquid chromatography, gas chromatography, thin layer chromatography etc.), particularly preferably uses high performance liquid chromatography to measure.By using high performance liquid chromatography, can be under the same conditions, use same sample, with the amount of high sensitivity measuring limaprost and 11-deoxidant body, 8-isomer.High performance liquid chromatography is undertaken by known method.
Particularly, according to the experimental condition of high performance liquid chromatography (HPLC) below, carry out.By using this law, can measure the amount of limaprost and catabolite, calculate the ratio of limaprost and catabolite.
the experimental condition of HPLC:
Detector: ultraviolet light absorption photometer (mensuration wavelength: 215nm);
Post: to the phase chromatography-use octadecyl silylanizing silica gel of filling 3～5 μ m in the stainless steel tube of the about 5mm of internal diameter, length 10～20cm;
Mobile phase: 0.02M potassium dihydrogen phosphate (pH4.3)/acetonitrile/isopropyl alcohol mixed liquor (9:5:2);
Flow: the retention time of adjusting limaprost is approximately 12 minutes;
Inner mark solution: the acetonitrile solution of testosterone (13 → 20000).
As mentioned above, the amount of catabolite also can be measured by the known method except high performance liquid chromatography, in addition, even if be high performance liquid chromatography, also can use other condition determination, other computational methods (for example, external standard method etc.) to evaluate.Use described high performance liquid chromatography method in addition, in the stability test under for example 30 ℃ of temperature, relative humidity 75%, even preserve 30 days or the growing amount of the 11-deoxidant body after month for surpassing 5% amount, if the growing amount that uses said method 11-deoxidant body for more than detectability approximately below 5%, be also contained in the present invention.And then the unmeasured in fact situation of 11-deoxidant body is also contained in the present invention.
In the present invention, the cyclodextrin as with limaprost combination, in the cyclodextrin such as alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin and hydroxypropylβ-cyclodextrin, is used beta-schardinger dextrin-especially.
The fitting method of beta-schardinger dextrin-, can mix the inclusion compound (limaprost alfadex) of limaprost or the limaprost that obtained by alpha-cyclodextrin and beta-schardinger dextrin-by known method.In the present invention, while mixing beta-schardinger dextrin-, do not add solvent etc., as long as mix, add beta-schardinger dextrin-under the condition that does not have solvent.
In addition, about the fitting method of beta-schardinger dextrin-, also can after making the lyophilizing body that contains limaprost or limaprost alfadex and beta-schardinger dextrin-, be pulverized to use.The lyophilizing body that contains limaprost or limaprost alfadex and beta-schardinger dextrin-, (for example water, organic solvent are (for example can be for example limaprost or limaprost alfadex and beta-schardinger dextrin-to be dissolved in to solvent, ethanol, acetone etc.) etc.) in, according to conventional method, manufacture.In addition, fitting method about beta-schardinger dextrin-, also can in the lyophilizing body that contains limaprost or limaprost alfadex and beta-schardinger dextrin-, further mix interpolation beta-schardinger dextrin-, for example, after the lyophilizing body of manufacturing by said method is pulverized, further mix beta-schardinger dextrin-.
Fitting method as the beta-schardinger dextrin-in the present invention, can coordinate by any means, preferably comprise following operation: when mixing beta-schardinger dextrin-, do not add water or organic solvent etc., under the condition that does not have solvent, mix and add beta-schardinger dextrin-, particularly preferably the lyophilizing body that contains limaprost or limaprost alfadex and beta-schardinger dextrin-is pulverized, more further mixed beta-schardinger dextrin-.
In the situation that the quality of tablet integral body is made as to 100%, the cooperation containing ratio of beta-schardinger dextrin-is approximately 30 quality %～99 quality % preferably, 50 quality %～95 quality % more preferably from about, further preferred approximately 50 quality %～85 quality %.At this, the use level of beta-schardinger dextrin-refers to: the beta-schardinger dextrin-adding while manufacturing lyophilizing body and the total amount of mixing the beta-schardinger dextrin-adding, the i.e. total amount of contained beta-schardinger dextrin-in tablet integral body.
In the situation that the lyophilizing body that contains limaprost and beta-schardinger dextrin-is pulverized and the further beta-schardinger dextrin-that mixes, the beta-schardinger dextrin-that the lyophilizing body that manufacture contains limaprost and beta-schardinger dextrin-is used is trace, the quality of tablet integral body is made as to 100 quality %, it is approximately 0.1～1 quality %, preferably approximately 0.1～0.5 quality %.On the other hand, the quality of tablet integral body is made as to 100 quality %, mixing the beta-schardinger dextrin-adding is approximately 30～99 quality %, preferred approximately 50～95 quality %, further preferred approximately 50～85 quality %.
The stability that the tablet that contains limaprost and beta-schardinger dextrin-is very high with respect to humidity display, the optional glucan (dextran etc.) that further coordinates.By coordinating glucan, also can improve with respect to hot stability.In this description, glucan refer to glucosan or with chemical method or enzyme process, glucosan is processed after the material that obtains.The general name that glucosan is the polysaccharide that consists of D-Glucose, is divided into alpha-glucans and beta glucan.As alpha-glucans, can enumerate: have α 1 → 4 glycosidic bond glucosan (such as starch, glycogen etc.), there is the glucosan (dextran etc.) of α 1 → 6 glycosidic bond or there is α 1 → 4 and the glucosan of α 1 → 6 glycosidic bond (for example, pulullan etc.) etc.As the representative substances of beta glucan, for example, can enumerate: the cellulose of β 1 → 4 glycosidic bond etc.As the material obtaining after glucosan being processed with chemical method or enzyme process, the saccharide for example, obtaining after with chemical method or enzyme process, starch being processed, can enumerate such as dextrin or pregelatinized Starch etc.In the present invention, as preferred glucan, can enumerate: dextran (for example, dextran, Dextran 40, macrodex etc.), dextrin, pulullan, corn starch, potato starch, wheaten starch, rice fecula, pregelatinized Starch etc., particularly preferably dextran.Fitting method as glucan, can coordinate merely, also can for example, for example,, by for example limaprost, beta-schardinger dextrin-and glucan being dissolved in solvent (water, organic solvent (, ethanol, acetone etc.) etc.), according to common method, manufacture lyophilizing body and coordinate.In the situation that having coordinated glucan, with respect to hot stability, improve, but there is the tendency with respect to the bad stability of humidity, therefore, the glucan amount coordinating is trace, if using tablet integral body as 100 quality %, it is approximately 0.0165～2.5 quality %, preferred approximately 0.0165～1.0 quality %, further preferred approximately 0.08～1.0 quality %.In addition, the in the situation that of coordinating glucan in tablet, the mixing ratio of limaprost alfadex and dextran is preferably limaprost alfadex: dextran=1:0.1～15, limaprost alfadex more preferably: dextran=1:0.1～6, in addition, limaprost alfadex more preferably: dextran=1:0.5～6.Further, by coordinating glucan, the hardness of lyophilizing body increases, and the formability of tablet is also improved.
Tablet of the present invention (for example, plain sheet, have core sheet, coated tablet, three-layer tablet etc.), except above-mentioned additive, also can further contain additive.As additive, as long as common used material when manufacturing tablet, such as can being suitablely used in conjunction with one or more in excipient, lubricant, disintegrating agent, fluidizing reagent, binding agent, correctives, flavoring agent, surfactant, spice, coloring agent, antioxidant, screening agent, antistatic additive, wetting agent etc.
As excipient, can enumerate: for example, glucose, fructose, maltose, lactose (lactose hydrate, spray-dried lactose, fluidized bed pelletize lactose, isomerized lactose, reduction lactose etc.), sucrose, PEARLITOL 25C, erythritol, maltose alcohol, xylitol, palatinose, trehalose, Sorbitol, crystalline cellulose, Talcum, silicic acid anhydride, anhydrous calcium phosphate, winnofil, calcium silicates etc.As lubricant, can enumerate such as magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, Talcum, Polyethylene Glycol etc.As disintegrating agent, can enumerate such as low degree of substitution hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, hydroxypropyl starch, corn starch etc.As fluidizing reagent, can enumerate such as light silicon anhydride, Talcum, aqueous silicon dioxide etc.As binding agent, such as hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethyl cellulose, sodium alginate, arabic gum powder, gelatin etc. can be enumerated, wherein a kind of or two or more can be suitablely used in conjunction with.As correctives, can enumerate such as white sugar, D-Sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, Talin, saccharin sodium, glycyrrhizic acid dipotassium, sodium glutamate, 5'-inosinic acid sodium, GMP etc.As flavoring agent, can enumerate such as trehalose, malic acid, maltose, potassium gluconate, fennel essential oil, Rhizoma et radix valerianae quintessence oil, Elettaria cardamomum (L.) Maton quintessence oil etc.As surfactant, can enumerate such as Polysorbate (polyoxyethylene sorbitan monoleate etc.), poloxalkol, sodium lauryl sulphate etc.As spice, can enumerate for example Fructus Citri Limoniae oil, orange oil, menthol, Herba Menthae wet goods.As coloring agent, can enumerate such as titanium oxide, edible Sunset Yellow FCF, No. 2, edible blueness, iron sesquioxide, yellow iron sesquioxide etc.As antioxidant, can enumerate such as sodium ascorbate, Cys, sodium sulfite, vitamin E etc.As screening agent, can enumerate such as titanium oxide etc.As antistatic additive, can enumerate such as Talcum, titanium oxide etc.As wetting agent, can enumerate such as polyoxyethylene sorbitan monoleate, dodecyl acid sodium sulfate, sucrose fatty acid ester, Polyethylene Glycol, hydroxypropyl cellulose (HPC) etc.
Tablet of the present invention can be manufactured by method below.For example, by limaprost, limaprost alfadex or the lyophilizing body ground product that contains limaprost; use the pelletizes such as rotary pelleting machine, stirring granulating machine, fluidized granulation machine, centrifugal rotation comminutor, Drygranulatemachine; and additive package equably in the granule obtaining thus as required; utilize the compression formings such as rotary tablet machine to obtain plain sheet; this element sheet directly can be used as tablet, also can further use as required coating base to be coated.In addition, also can not carry out pelletize and prepare containing limaprost, limaprost alfadex or the lyophilizing body ground product that contains limaprost and the mixed-powder of additive, utilize rotary tablet machine etc. to carry out tabletting to it.Tablet of the present invention unexpectedly tool has the following advantages: although contain the relatively large beta-schardinger dextrin-of disintegrative that likely brings to tablet etc., it is no problem to have aspect formability.
In addition, lubricant also can mix by internal lubrication or external lubrication method.
Tablet of the present invention can be dried before tabletting or after tabletting.As the drying means of tablet, preferred hot air drying, drying under reduced pressure or heating drying under reduced pressure.
As the drying means of tablet, preferred drying under reduced pressure or heating drying under reduced pressure.
Tablet of the present invention is to treatment peripheral circulation disorders, very effective such as the treatment of Buerger's disease or lumbar spinal stenosis etc.
Invention effect
Tablet of the present invention is highly stable with respect to humidity, can suppress the generation of limaprost analyte, therefore can long preservation, and in addition, the formability aspect of tablet is also no problem.Therefore, tablet of the present invention can with the state of other medicament one packetize for clinical.
The specific embodiment
Below, formulation example and experimental example are shown as embodiment, but these examples are for deep understanding example of the present invention, not delimit the scope of the invention.
experimental example 1: the stability comparison in various additives
(1) manufacture of lyophilizing body
In 37.5g pure water, dissolve 1g limaprost alfadex, then dissolve 7g Dextran 40.This liquid is moved to metal tray, by common method lyophilizing.After lyophilizing, utilize mortar to pulverize, use sieve (No. 42 sieves) to sieve, obtain lyophilizing body powder.
(2) preparation of mixed-powder
Utilize mortar to mix above-mentioned limaprost alfadex/Dextran 40 lyophilizing body (200mg) and various additive (15g), then the amount with each 1g is divided in vial.Use pressure Reduction Dryer to be dried (50 ℃, more than 12 hours) to the sample of subpackage, then under the state of uncapping, sample is placed in the stabilization testing machine of 30 ℃ of temperature, relative humidity 75%, regularly sampling is evaluated.
(3) purity test
By high performance liquid chromatography (HPLC), analyze the production rate of the catabolite (11-deoxidant body) of limaprost.
Result is as follows.
[table 1]
| Additive | During beginning | Two weeks | One month |
| Lactose | 0.9 | 6.6 | 13.9 |
| Calcium phosphate dibasic anhydrous | 0.5 | 4 | 7.6 |
| Hardened rapeseed oil | 1.3 | 3.8 | 7.4 |
| Stearic acid | 0.9 | 4.2 | 8.2 |
| Macrodex | 0.6 | 3.8 | 6.8 |
| Aspartic acid | 1.7 | 4.3 | 8.6 |
| Alpha-cyclodextrin | 1.8 | 4.8 | 9.9 |
| Beta-schardinger dextrin- | - | 2.6 | 4.4 |
In the situation that beta-schardinger dextrin-has been added in mixing, after two weeks, catabolite is below 3%, and preserving one month is still below 5% afterwards.On the other hand, for take the powder that other additive that alpha-cyclodextrin is representative and limaprost mix, its catabolite through time increase, preserve after one month, substantially exceed 5%.
Therefore, show that, in the mixed-powder of beta-schardinger dextrin-and limaprost, the stability of limaprost is improved.
experimental example 2: the impact of the beta-schardinger dextrin-content in tablet
< formulation example 1: the tablet > that the content of beta-schardinger dextrin-is 30%
In 62.25g pure water, dissolve 1.67g limaprost alfadex, add 1.67g beta-schardinger dextrin-and dissolve, then dissolving 3.32g Dextran 40.This liquid is moved in metal tray, by common method lyophilizing.After lyophilizing, utilize mortar to pulverize, use sieve (No. 30 sieves) to sieve, obtain lyophilizing body powder.
To O.664g mixing 20g carboxymethyl cellulose, 30g beta-schardinger dextrin-, 50g lactose, 0.2g light silicon anhydride, 2g stearic acid in above-mentioned lyophilizing body powder, use rotary tablet machine (chrysanthemum water is made institute's (strain) system) with 800～1000kg/cm
2tabletting pressure carry out tabletting (a slice 102.9mg, 6.5mm Φ), obtain thus 1000, every tablet of tablet that contains 5 μ g limaprosts.
< formulation example 2: the tablet > that the content of beta-schardinger dextrin-is 50%
In the 0.664g lyophilizing body powder same with formulation example 1, mix 20g carboxymethyl cellulose, 50g beta-schardinger dextrin-, 30g lactose, 0.2g light silicon anhydride, use rotary tablet machine (chrysanthemum water is made institute's (strain) system) with 800～1000kg/cm
2tabletting pressure carry out tabletting (a slice 100.9mg, 6.5mm Φ), obtain thus 1000, every tablet of tablet that contains 5 μ g limaprosts.Use external lubrication device (chrysanthemum water is made institute's (strain) system) that magnesium stearate is sprayed in tablet machine.
< formulation example 3: the tablet > that the content of beta-schardinger dextrin-is 60%
In the 0.664g lyophilizing body powder g same with formulation example 1, mix 20g carboxymethyl cellulose, 60g beta-schardinger dextrin-, 20g lactose, 0.2g light silicon anhydride, use rotary tablet machine (chrysanthemum water is made institute's (strain) system) with 800～1000kg/cm
2tabletting pressure tabletting (a slice 100.9mg, 6.5mm Φ), obtain thus 1000, every tablet of tablet that contains 5 μ g limaprosts.Use external lubrication device (chrysanthemum water is made institute's (strain) system) that magnesium stearate is sprayed in tablet machine.
< formulation example 4: the tablet > that the content of beta-schardinger dextrin-is 70%
In the 0.664g lyophilizing body powder same with formulation example 1, mix 20g carboxymethyl cellulose, 70g beta-schardinger dextrin-, 10g lactose, 0.2g light silicon anhydride, use rotary tablet machine (chrysanthemum water is made institute's (strain) system) with 800～1000kg/cm
2tabletting pressure carry out tabletting (a slice 100.9mg, 6.5mm Φ), obtain thus 1000, every tablet of tablet that contains 5 μ g limaprosts.Use external lubrication device (chrysanthemum water is made institute's (strain) system) that magnesium stearate is sprayed in tablet machine.
< formulation example 5: the tablet > that the content of beta-schardinger dextrin-is 80%
In the 0.664g lyophilizing body powder same with formulation example 1, mix 20g carboxymethyl cellulose, 80g beta-schardinger dextrin-, 0.2g light silicon anhydride, use rotary tablet machine (chrysanthemum water is made institute's (strain) system) with 800～1000kg/cm
2tabletting pressure carry out tabletting (a slice 100.9mg, 6.5mm Φ), obtain thus 1000, every tablet of tablet that contains 5 μ g limaprosts.Use external lubrication device (chrysanthemum water is made institute's (strain) system) that magnesium stearate is sprayed in tablet machine.
< formulation example 6: the tablet > that the content of beta-schardinger dextrin-is 90%
In the 0.664g lyophilizing body powder same with formulation example 1, mix 10g carboxymethyl cellulose, 90g beta-schardinger dextrin-, 0.2g light silicon anhydride, use rotary tablet machine (chrysanthemum water is made institute's (strain) system) with 800～1000kg/cm
2tabletting pressure carry out tabletting (a slice 100.9mg, 6.5mm Φ), obtain thus 1000, every tablet of tablet that contains 5 μ g limaprosts.Use external lubrication device (chrysanthemum water is made institute's (strain) system) that magnesium stearate is sprayed in tablet machine.
< comparative formulations example 1>
Utilize the method manufacture comparative formulations example 1 identical with the embodiment 13 of No. 3646310th, Japan Patent.
< comparative formulations example 2: beta-schardinger dextrin-content is the tablet > of 0.2% (mixing addition 0%)
In the 0.664g lyophilizing body powder same with formulation example 1, mix 20g carboxymethyl cellulose, 80g lactose, 0.2g light silicon anhydride, use rotary tablet machine (chrysanthemum water is made institute's (strain) system) with 800～1000kg/cm
2tabletting pressure carry out tabletting (a slice 102.9mg, 6.5mm Φ), obtain thus 1000, every tablet of tablet that contains 5 μ g limaprosts.
The prescription of above-mentioned formulation example 1～6, comparative formulations example 1 and 2 is shown in to following table.
By each prescription, approximately 100 be filled in vial, under the state of uncapping, be placed in the stabilization testing machine of 30 ℃ of temperature, relative humidity 75%, regularly sampling, tablet is evaluated.By high performance liquid chromatography (HPLC), analyze the production rate of the catabolite (11-deoxidant body) of limaprost.
By limaprost and analyte and be made as 100, calculate the production rate of analyte.Analysis result is shown in following.
[table 3]
| ? | Beta-schardinger dextrin-content (%) | During beginning | One month |
| Comparative formulations example 1 | 0 | 0.3 | 9.1 |
| Comparative formulations example 2 | 0.2 | 1.1 | 6.7 |
| Formulation example 1 | 30 | 0.3 | 3.9 |
| Formulation example 2 | 50 | 0.9 | 3.1 |
| Formulation example 3 | 60 | 0.8 | 2.9 |
| Formulation example 4 | 70 | 0.8 | 2.7 |
| Formulation example 5 | 80 | 0.7 | 2.4 |
| Formulation example 6 | 90 | 0.7 | 2.6 |
With in tablet not containing the tablet (comparative formulations example 1) of recording in the embodiment 13 of the patent documentation 1 of beta-schardinger dextrin-and contain with the comparative formulations example 2 of the beta-schardinger dextrin-of the alpha-cyclodextrin equivalent of enclose limaprost in lyophilizing body and compare, add more than 30% beta-schardinger dextrin-and significantly improve as the stability of the tablet (formulation example 1-6) of additive.
Therefore, the tablet of more than 30% beta-schardinger dextrin-of mixing interpolation shows that storage stability is improved.
experimental example 3: add the impact of glucan on heat stability
Use the tablet of the following various dextran content that form of the method manufacture same with formulation example 1, formulation example 7～13.
The tablet obtaining is encased in vial, and the vial after this filling (1) is kept to the stabilizing test device of 30 ℃ of temperature, relative humidity 75% and (2) under the state of uncapping, and under the condition of sealing lid, to be kept at temperature be in the stabilizing test device of 60 ℃.Through time preparation is sampled, utilize high performance liquid chromatography (HPLC) to analyze the production rate (11-deoxidant body production rate (%)) of the catabolite of limaprost.By limaprost and analyte and be made as 100, calculate the production rate of analyte.Analysis result is as follows.
[table 5]
As mentioned above, tablet improves along with the dextran content in lyophilizing body with respect to hot stability.
industrial applicibility
The tablet that contains limaprost of the present invention is highly stable with respect to humidity.Therefore, can with other preparation one packetize, can quality do not occur deterioratedly for clinical, therefore, very effective as medicine.
Claims (13)
1. tablet, it contains limaprost and beta-schardinger dextrin-,
Wherein, using tablet integral body as 100 quality %, contain the beta-schardinger dextrin-of 30～99 quality %.
2. tablet according to claim 1, wherein, using tablet integral body as 100 quality %, contains the beta-schardinger dextrin-of 50～95 quality %.
3. according to the tablet described in any one in claim 1～2, it optionally further contains the glucan of 0.0165～2.5 quality %.
4. according to the tablet described in any one in claim 1～3, wherein, limaprost is contained in described tablet with the form of limaprost alfadex, and wherein this tablet at least contains:
(1) mixture of the beta-schardinger dextrin-in the lyophilizing body that comprises limaprost alfadex and (2).
5. tablet according to claim 4, it is manufactured by comprising following operation:
Under the condition that does not have solvent, mix the operation of adding (2) beta-schardinger dextrin-.
6. tablet according to claim 5 wherein, further contains beta-schardinger dextrin-in lyophilizing body.
7. tablet according to claim 6, wherein, using tablet integral body as 100 quality %, the beta-schardinger dextrin-in lyophilizing body is 0.1～1 quality %.
8. according to the tablet described in any one in claim 4～7, wherein, in lyophilizing body, further contain glucan.
9. tablet according to claim 8, wherein, contains limaprost alfadex and glucan with the ratio of 1:0.1～15.
10. tablet according to claim 8, wherein, contains limaprost alfadex and glucan with the ratio of 1:0.1～6.
11. tablets, it contains limaprost alfadex, beta-schardinger dextrin-and glucan,
Wherein, using tablet integral body as 100 quality %, contain the beta-schardinger dextrin-of 30～99 quality %, the glucan of 0.0165～2.5 quality %.
12. tablets, it contains: the mixture of the lyophilizing body that (1) comprises limaprost alfadex, beta-schardinger dextrin-and glucan and (2) beta-schardinger dextrin-,
Wherein, using tablet integral body as 100 quality %, contain the beta-schardinger dextrin-of 30～99 quality %, the glucan of 0.0165～1.0 quality %.
13. according to the tablet described in any one in claim 1～12, wherein, under the condition of 30 ℃ of temperature, relative humidity 75%, preserves after one month, does not contain in fact 17S, 20-dimethyl-trans-Δ in tablet
2-PGA
1, or using tablet integral body as 100%, 17S, 20-dimethyl-trans-Δ
2-PGA
1be below 5%.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2011-125304 | 2011-06-03 | ||
| JP2011125304A JP4890657B1 (en) | 2011-06-03 | 2011-06-03 | Tablet containing Limaprost and β-cyclodextrin |
| PCT/JP2012/064297 WO2012165621A1 (en) | 2011-06-03 | 2012-06-01 | TABLET CONTAINING LIMAPROST AND β-CYCLODEXTRIN |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103619339A true CN103619339A (en) | 2014-03-05 |
| CN103619339B CN103619339B (en) | 2015-06-17 |
Family
ID=45907884
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201280027255.6A Active CN103619339B (en) | 2011-06-03 | 2012-06-01 | Tablet containing limaprost and ss-cyclodextrin |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP4890657B1 (en) |
| KR (1) | KR101504862B1 (en) |
| CN (1) | CN103619339B (en) |
| HK (1) | HK1191576A1 (en) |
| MY (1) | MY166053A (en) |
| WO (1) | WO2012165621A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109071427A (en) * | 2016-05-09 | 2018-12-21 | Ａｇｃ株式会社 | Novel derivatives of prostaglandins |
| CN115666532A (en) * | 2020-05-28 | 2023-01-31 | 研成精密化学株式会社 | Sustained release preparation containing limaprost |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101967199B1 (en) | 2017-01-24 | 2019-04-09 | 환인제약 주식회사 | Stability improved pharmaceutical composition comprising limaprost by using fluid-bed granulator |
| JP7004448B2 (en) * | 2017-11-13 | 2022-01-21 | 沢井製薬株式会社 | Lymaprost-containing lyophilized composition and Limaprost-containing pharmaceutical composition |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6152146B2 (en) * | 1981-03-20 | 1986-11-12 | Ono Pharmaceutical Co | |
| CN1298311A (en) * | 1998-03-31 | 2001-06-06 | 永进药品工业株式会社 | A drug composition containing sodium Pravastatin |
| JP2006052156A (en) * | 2004-08-10 | 2006-02-23 | Ono Pharmaceut Co Ltd | Pharmaceutical composition for oral administration |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS503362B1 (en) * | 1970-06-10 | 1975-02-04 | ||
| JPS5231404B1 (en) * | 1971-04-28 | 1977-08-15 | ||
| JPS5486607A (en) * | 1977-12-23 | 1979-07-10 | Yoshinobu Nakai | Solid pharmaceutical composition |
| JP2521612B2 (en) * | 1992-05-20 | 1996-08-07 | ウエイ・ミン・フアーマシユーテイカル・マニユフアクチヤリング・カンパニー・リミテツド | Direct tablet forming aid |
| JP2005139086A (en) * | 2003-11-04 | 2005-06-02 | Ono Pharmaceut Co Ltd | Quick-disintegration preparation |
| WO2007072497A2 (en) * | 2005-12-02 | 2007-06-28 | Alembic Limited | Stabilized pharmaceutical composition of pramipexole and method of preparation thereof |
| KR20080099562A (en) * | 2007-05-10 | 2008-11-13 | 박은석 | Pharmaceutical composition comprising stabilized solid-dispersion |
| CN101862337B (en) * | 2010-05-28 | 2012-03-21 | 北京泰德制药股份有限公司 | Drug composite containing limaprost and preparation method thereof |
-
2011
- 2011-06-03 JP JP2011125304A patent/JP4890657B1/en active Active
-
2012
- 2012-06-01 MY MYPI2013702287A patent/MY166053A/en unknown
- 2012-06-01 WO PCT/JP2012/064297 patent/WO2012165621A1/en active Application Filing
- 2012-06-01 KR KR1020137031576A patent/KR101504862B1/en active IP Right Grant
- 2012-06-01 CN CN201280027255.6A patent/CN103619339B/en active Active
-
2014
- 2014-05-28 HK HK14105031.4A patent/HK1191576A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6152146B2 (en) * | 1981-03-20 | 1986-11-12 | Ono Pharmaceutical Co | |
| CN1298311A (en) * | 1998-03-31 | 2001-06-06 | 永进药品工业株式会社 | A drug composition containing sodium Pravastatin |
| JP2006052156A (en) * | 2004-08-10 | 2006-02-23 | Ono Pharmaceut Co Ltd | Pharmaceutical composition for oral administration |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109071427A (en) * | 2016-05-09 | 2018-12-21 | Ａｇｃ株式会社 | Novel derivatives of prostaglandins |
| AU2017264102B2 (en) * | 2016-05-09 | 2020-09-24 | AGC Inc. | Novel prostaglandin derivative |
| CN115666532A (en) * | 2020-05-28 | 2023-01-31 | 研成精密化学株式会社 | Sustained release preparation containing limaprost |
| CN115666532B (en) * | 2020-05-28 | 2024-06-11 | 研成精密化学株式会社 | Sustained release preparation containing limaprost |
Also Published As
| Publication number | Publication date |
|---|---|
| HK1191576A1 (en) | 2014-08-01 |
| KR20140029467A (en) | 2014-03-10 |
| WO2012165621A1 (en) | 2012-12-06 |
| MY166053A (en) | 2018-05-22 |
| KR101504862B1 (en) | 2015-03-20 |
| JP4890657B1 (en) | 2012-03-07 |
| CN103619339B (en) | 2015-06-17 |
| JP2014080368A (en) | 2014-05-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Mizumoto et al. | Formulation design of a novel fast-disintegrating tablet | |
| JP5255429B2 (en) | Pharmaceutical composition containing oseltamivir phosphate | |
| CN104719910B (en) | EGCG solid dispersion compositions with heat endurance and its preparation method and application | |
| CN103619339B (en) | Tablet containing limaprost and ss-cyclodextrin | |
| Sruti et al. | Improvement in the dissolution rate and tableting properties of cefuroxime axetil by melt-granulated dispersion and surface adsorption | |
| DK2885005T3 (en) | FIXED PHARMACEUTICAL PREPARATION CONTAINING LEVOTHYROXIN | |
| Miller et al. | Inulin as microencapsulating agent improves physicochemical properties of spray-dried aspalathin-rich green rooibos (Aspalathus linearis) extract with α-glucosidase inhibitory activity | |
| EP2668852B1 (en) | Composition for oral administration | |
| JP6853192B2 (en) | α, α-trehalose dihydrous crystal-containing powder and its production method and application | |
| JP2005314413A (en) | Medicine composition for oral administration | |
| EP3875088A1 (en) | Package for medical composition containing anti-tumor agent | |
| CN114432424A (en) | Stable aluminum-plastic packaged desmopressin tablet | |
| CN102327233A (en) | Dimercaptosuccinic acid granular formulation | |
| CN114377147A (en) | Alvatripopa clathrate compound, composition and preparation method thereof | |
| JP3646310B1 (en) | Pharmaceutical composition for oral administration | |
| TWI508753B (en) | For the manufacture of beta-cyclodextrin (LIMAPROST) preparations | |
| JP7004448B2 (en) | Lymaprost-containing lyophilized composition and Limaprost-containing pharmaceutical composition | |
| JP2006045218A (en) | Medicinal composition for oral administration | |
| JP2008074838A (en) | Glucosyl hesperidin-containing composition | |
| JP5553522B2 (en) | Pharmaceutical composition for oral administration | |
| JP2005272458A (en) | Medical composition for oral administration | |
| RU2748311C1 (en) | Pharmaceutical composition containing solid dispersions of amorphous cladribine and pharmaceutically acceptable water-soluble carrier | |
| KR100833211B1 (en) | Pharmaceutical Composition for Oral Administration | |
| Magar | FORMULATION AND EVALUTION OF ORAL DISPERSIBLE TABLETS | |
| WO2023120558A1 (en) | Method for storing reduced coenzyme q10 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1191576 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1191576 Country of ref document: HK |