CN1273861A - Low sustituted ethylene-lactic cellulose and solid preparation - Google Patents
Low sustituted ethylene-lactic cellulose and solid preparation Download PDFInfo
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- CN1273861A CN1273861A CN00108581A CN00108581A CN1273861A CN 1273861 A CN1273861 A CN 1273861A CN 00108581 A CN00108581 A CN 00108581A CN 00108581 A CN00108581 A CN 00108581A CN 1273861 A CN1273861 A CN 1273861A
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- tablet
- low degree
- hydroxypropyl cellulose
- substitution hydroxypropyl
- disintegration time
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B11/00—Preparation of cellulose ethers
- C08B11/02—Alkyl or cycloalkyl ethers
- C08B11/04—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals
- C08B11/08—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals with hydroxylated hydrocarbon radicals; Esters, ethers, or acetals thereof
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- 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
- A61K47/38—Cellulose; Derivatives thereof
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The present invention can improve the wettability and significantly shorten the disintegration time of a solid formulation even in the same amount added and formulating composition as those of a conventional formulation by using a specific hydroxypropyl cellulose having a low degree of substitition. A hydroxypropyl cellulose having a low degree of substitution of 0.04-0.1 average number of substituted mol of hydroxypropoxyl groups based on the glucose unit is used.
Description
The present invention relates to a kind of low degree of substitution hydroxypropyl cellulose and the solid formulation that contains it, said low degree of substitution hydroxypropyl cellulose can improve wettability, form even used with in the past identical addition and cooperate, also can obviously shorten the disintegration time of solid formulation.
Low degree of substitution hydroxypropyl cellulose legally records as the pharmaceuticals additive in book many, is as disintegrating agent and widely used a kind of material.The purpose of adding disintegrating agent is to shorten the disintegration time of solid formulations such as tablet, granule, capsule.
The disintegrate of tablet is one of key factor of regulation bioavailability of medicament.The absorption of medicine in the digestive tract is along with disintegrate, the dissolving of medicine in digestive tract liquid of tablet are carried out.In recent years, from the viewpoint of the effective utilization and the congruency evaluation of medicine, begin to reappraise the dissolution test of solid formulations such as tablet, the preparation that stripping is fast can be guaranteed effectiveness or equivalence.Therefore, for tablet, just at a kind of disintegrate of demand tablet faster.
Present widely used disintegrating agent has cellulose derivatives such as carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose, low degree of substitution hydroxypropyl cellulose, starch derivatives such as carboxymethyl starch sodium, part alphalysed starch, synthetic high polymers such as cross-linking polyethylene pyrrolidone.Judge the selection disintegrating agent according to the disintegrate power (swelling power) of each disintegrating agent, mouldability, hygroscopicity, retention of color, the cooperation adaptability that is suitable for medicine.
Especially, low degree of substitution hydroxypropyl cellulose has nonionic, hygroscopicity is low, retention of color is good, with the advantages such as adaptability is good of cooperating of many medicaments, but for the medicament of some kind and the prescription of some kind, compare with other additives, it can't shorten disintegration time sometimes to object time, is therefore just seeking to improve its this shortcoming.
The disintegrate mechanism of the tablet that is made of powder particle is, liquid (water) such as digestive tract liquid enter tablet inside by capillary tube, water-soluble substances hydrolysis then, and disintegrating agents etc. are by water-wet, the granule swelling, effect makes the formation Dispersion of Particles thus.Therefore, water enters the 1st stage that tablet inside is disintegration of tablet.
Said water enters the speed of tablet inside, shown in following Washburn formula, the factor relevant with tablet (R), the factor (γ, η) relevant with test solution, factor (θ) intricately relevant with the two link together and (preparation design method (1), know people's book shop, p 507, (1971).
L2＝{(Rγcosθ)/(2η)}t
(in the formula, L is a capillary pipe length wetted in time t, and R is a capillary radius, and γ is the surface tension of liquid, and η is the viscosity of liquid, and θ is a solid liquid interface contact angle.)
The disintegration time of tablet be subjected to kind, use level of medicament etc. about, under the restriction of purpose tablet size, medicament use level etc., the preparation of the disintegration time that is difficult to achieve the goal is quite a few.As the general maneuver that makes the rapid disintegrate of tablet, the addition that increases disintegrating agent, the methods such as voidage that increase tablet inside are arranged.But the method that increases the disintegrating agent addition can make tablet become big, and it is limited to improve effect, and on the other hand, the method that increases voidage is that the forming pressure when being configured as tablet by the reduction compressing powder realizes, but the shortcoming that also exists tablet hardness to reduce.
The disintegration time of tablet, form at tablet, the use level of disintegrating agent etc. is identical, be under the occasion that space (capillary radius) is identical, environment (experimental liquid) is identical of tablet inside,, only be subjected to the domination of wettability (Gu-liquid interface contact angle) according to aforesaid Washburn formula.
From people's such as Gissinger report (Drug Dev.Ind.Pharm, 6 (5), 511-536,1980) as can be known, low degree of substitution hydroxypropyl cellulose is compared with other additive, wettability low (contact angle is big).For example, low degree of substitution hydroxypropyl cellulose is 50 °, and is that to improve the microcrystalline Cellulose that the formability of tablet adds be about 20 °, cross-linking sodium carboxymethyl cellulose is 0 °, and carboxymethyl starch sodium is 0 °, and the part alphalysed starch is 0 °, crospolyvinylpyrrolidone is 34 °, and wettability is all very poor.
The object of the present invention is to provide a kind of low degree of substitution hydroxypropyl cellulose and contain this cellulosic solid formulation, said low degree of substitution hydroxypropyl cellulose can improve wettability, even with before same addition, cooperate under the condition of forming, also can significantly shorten the disintegration time of solid formulation.
The inventor etc. have carried out deep research for addressing these problems, found that, the average replacement molal quantity of the propoxyl of every glucose unit is that 0.04～0.1 low degree of substitution hydroxypropyl cellulose and the solid formulation that contains it can improve wettability, even with before same addition, cooperate under the condition of forming, also can significantly shorten the disintegration time of solid formulation, thereby finish the present invention.
Low degree of substitution hydroxypropyl cellulose of the present invention and the solid formulation that contains it can improve wettability, though with before same addition, cooperate under the condition of forming, also can significantly shorten the disintegration time of solid formulation.
Low degree of substitution hydroxypropyl cellulose of the present invention can be opened clear 48-38858 communique, spy according to the spy, and to open in the clear 57-53100 communique disclosed method synthetic.
In general, hydroxypropyl cellulose is meant every glucose unit (C
6H
10O
5) the average replacement molal quantity of propoxyl is 2.0～4.2 material, on average replace molal quantity and be 0.11～0.39 material and be called low degree of substitution hydroxypropyl cellulose.
On the other hand, the average replacement molal quantity of the propoxyl in the low degree of substitution hydroxypropyl cellulose of the present invention is preferably every glucose unit 0.04～0.1.What propoxyl presented with respect to wettability is hydrophobic effect, and the replacement amount of propoxyl is low more, and hydrophilic is good more, when improving wettability, reduces as the swelling power of disintegrating agent.Therefore, if the average replacement molal quantity of propoxyl less than every glucose unit 0.04, then swelling power reduces significantly, and is not ideal enough, on the other hand, if greater than 0.1, then wettability is identical with existing low degree of substitution hydroxypropyl cellulose.In addition, can easily carry out by the addition of regulating the hydroxypropylation agent such as expoxy propane of reacting for the control of average replacement molal quantity with alkali cellulose.
The average replacement molal quantity of every glucose unit can be obtained the replacement % of propoxyl according to the quantitative method of the low degree of substitution hydroxypropyl cellulose of Japanese Pharmacopoeia, and converting obtains again.
Low degree of substitution hydroxypropyl cellulose of the present invention is applicable to any solid formulation that requires to shorten disintegration time.For example, in the manufacturing of tablet, can when the pelletize of tabletting powder, add, also can mix in the tabletting powder after pelletize.In addition, in the manufacture process of granule, can in pelletize is formed, add, in the manufacture process of capsule, can mix being engaged in the capsule charge powder.
In the solid formulation, except that low degree of substitution hydroxypropyl cellulose of the present invention, for example can also contain excipient such as lubricants such as principal agent, magnesium stearate, corn starch, lactose, other disintegrating agent, binding agent etc.That is,, also can use former cooperation to form even use low degree of substitution hydroxypropyl cellulose of the present invention.
Low degree of substitution hydroxypropyl cellulose of the present invention, when the binding agent of using as pelletize uses, with respect to dried solid formulation, preferred 3～15 weight % that add, when being mixed in tabletting powder after the pelletize or the capsule charge powder, preferred 3～10 weight % that add when using as excipient, preferably add more than the 30 weight %.That is, can with before use in the identical use level scope.
The maneuver that can implement to allow on the preparation to the solid formulation of as above making is film coating or enteric coating etc. for example.
Followingly illustrate in greater detail the present invention, but the present invention is not limited to embodiment according to embodiment and comparative example.Embodiment 1 (mensuration of wetting time)
In the 100ml beaker that has added the 50ml distilled water, drop into sample 500mg, measure the time of sample till by water surface moistening.(modulation of tabletting powder)
With acetyl aminophenol (Acetoaminophen) (micropowder, Yamamoto chemical industry society system) 400g, binding agent hydroxypropyl emthylcellulose (TC-SE, chemical industry society of SHIN-ETSU HANTOTAI system) 20g is dissolved in the 265g Purified Water, use small-sized fluidized bed prilling granulator (Multiplex MP-01, the Powerlex corporate system), presses well-established law, be modulated into prilling powder above-mentioned aqueous solution mist projection granulating.(low degree of substitutionization)
In the synthesis procedure of low degree of substitution hydroxypropyl cellulose, cut down the expoxy propane be used to react, by common condition, wash, dry, pulverize.The propoxyl of the powder that obtains on average replaces molal quantity, and to be every glucose unit 0.1. Powder Physical identical with the LH-11 that uses in the comparative example 1 described later.(modulation of tablet)
Above-mentioned acetyl aminophenol prilling powder 285g is fully mixed with 15g low degree of substitution hydroxypropyl cellulose (the average replacement molal quantity 0.1 of propoxyl), mix the magnesium stearate (SM-1000 of 6g then as lubricant, Sakai chemical industry society system), film-making tabletting powder.Use rotary tablet machine (RT-S15K-T35, chrysanthemum water is made made), with the drift of diameter 9mm, 12mm R, tabletting pressure 157MPa is pressed into the sheet of every 306mg.(evaluation of physical property)
According to the slaking test method of Japanese Pharmacopoeia, as experimental liquid, do not use rotating disk with Purified Water, measure the disintegration time of above-mentioned acquisition tablet.The wetting time of low degree of substitution hydroxypropyl cellulose and the disintegration time of tablet are shown in table 1.Comparative example 1
Use embodiment 1 synthetic acetyl aminophenol prilling powder and low degree of substitution hydroxypropyl cellulose (the average replacement molal quantity of propoxyl is 0.26 for LH-11, chemical industry society of SHIN-ETSU HANTOTAI system), at composition, the condition lower sheeting identical with embodiment 1.The wetting time of the low degree of substitution hydroxypropyl cellulose that obtains and the disintegration time of tablet are shown in table 1.Embodiment 2 (low degree of substitutionization)
On average replacing molal quantity with the same propoxyl that synthesizes the powder that obtains of embodiment is every glucose unit 0.05.The LH-11 that uses in Powder Physical and the comparative example 1 is identical.(modulation of tablet)
Use embodiment 1 synthetic acetyl aminophenol prilling powder, at the composition identical, same tabletting condition lower sheeting with embodiment 1.The wetting time of the low degree of substitution hydroxypropyl cellulose that obtains and the disintegration time of tablet are shown in table 1.Embodiment 3 (low degree of substitutionization)
It is every glucose unit 0.09 that the propoxyl of the synthetic similarly to Example 1 powder that obtains on average replaces molal quantity.That uses in Powder Physical and the comparative example 1 is identical.(modulation of tablet)
Use synthetic acetyl aminophenol prilling powder among the embodiment 1, at the composition identical, identical tabletting condition lower sheeting with embodiment 1.The wetting time of the low degree of substitution hydroxypropyl cellulose that obtains and the disintegration time of tablet are shown in table 1.Comparative example 2 (low degree of substitutionization)
It is every glucose unit 0.03 that the propoxyl of the synthetic similarly to Example 1 powder that obtains on average replaces molal quantity.The LH-11 that uses in Powder Physical and the comparative example 1 is identical.(modulation of tablet)
Use synthetic acetyl aminophenol prilling powder among the embodiment 1, at the composition identical, identical tabletting condition lower sheeting with embodiment 1.The wetting time of the low degree of substitution hydroxypropyl cellulose that obtains and the disintegration time of tablet are shown in table 1.
Table 1
Embodiment 4 (modulation of tablet)
| Hydroxypropyl cellulose | Tablet | ||
| The average replacement molal quantity/glucose unit of propoxyl | Wetting time | Disintegration time | |
| Embodiment 1 | ????0.1 | 4.9 second | 1 minute 44 seconds |
| Embodiment 2 | ????0.05 | 2.3 second | 2 minutes 4 seconds |
| Embodiment 3 | ????0.09 | 3.3 second | 1 minute 47 seconds |
| Comparative example 1 | ????0.26 | 11.2 second | 5 minutes 30 seconds |
| Comparative example 2 | ????0.03 | 0.8 second | 4 minutes 21 seconds |
Low degree of substitution hydroxypropyl cellulose 90g and GEGEN TANG extractum powder (GEGEN TANG powdered extract powder F with embodiment 1, Alps pharmaceutical industries corporate system) 210g fully mixes, mix magnesium stearate (SM-1000, Sakai chemical industry society system) 3g then, make the tabletting powder as lubricant.Use rotary tablet machine (RT-S15K-T35, chrysanthemum water is made made), use the drift of diameter 9mm, 12mm R, tabletting pressure 142MPa is pressed into the sheet of every 303mg.The wetting time of low degree of substitution hydroxypropyl cellulose and the disintegration time of tablet are shown in table 2.Embodiment 5
Use the low degree of substitution hydroxypropyl cellulose of embodiment 2, be modulated into tablet similarly to Example 4, measure disintegration time, the results are shown in table 2.Embodiment 6
Use the low degree of substitution hydroxypropyl cellulose of embodiment 3, be modulated into tablet similarly to Example 4, measure disintegration time.The results are shown in table 2.Comparative example 3
Use the LH-11 that uses in the comparative example 1, be modulated into tablet similarly to Example 4, measure disintegration time.The results are shown in table 2.Comparative example 4
Use the low degree of substitution hydroxypropyl cellulose of using in the comparative example 2, be modulated into tablet similarly to Example 4, measure disintegration time.The results are shown in table 2.
Table 2
| Hydroxypropyl cellulose | Tablet | ||
| The average replacement molal quantity/glucose unit of propoxyl | Wetting time | Disintegration time | |
| Embodiment 4 | ????0.1 | 4.9 second | 27.5 divide |
| Embodiment 5 | ????0.05 | 2.3 second | 33.2 divide |
| Embodiment 6 | ????0.09 | 3.3 second | 29.7 divide |
| Comparative example 3 | ????0.26 | 11.2 second | 47.5 divide |
| Comparative example 4 | ????0.03 | 0.8 second | 66.6 divide |
As shown in the Examples, low degree of substitution hydroxypropyl cellulose of the present invention is compared with known goods (comparative example 1), can significantly improve wettability, significantly shortens the disintegration time of tablet.
When the average replacement molal quantity of propoxyl is extremely low (comparative example 2,4), though can improve wettability, the effect that shortens disintegration time when making tablet significantly reduces, and has but prolonged on the contrary.This is considered to owing to extreme the reduction on average replaces the result that molal quantity causes reducing significantly swelling power.
Claims (2)
1. low degree of substitution hydroxypropyl cellulose is characterized in that, the average replacement molal quantity of the propoxyl of every glucose unit is 0.04～0.1.
2. solid formulation is characterized in that containing the low degree of substitution hydroxypropyl cellulose of putting down in writing in the claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP136788/1999 | 1999-05-18 | ||
| JP11136788A JP2000327701A (en) | 1999-05-18 | 1999-05-18 | Hydroxypropyl cellulose having low degree of substitution and solid formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1273861A true CN1273861A (en) | 2000-11-22 |
| CN1203896C CN1203896C (en) | 2005-06-01 |
Family
ID=15183542
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB001085816A Expired - Fee Related CN1203896C (en) | 1999-05-18 | 2000-05-18 | Low sustituted ethylene-lactic cellulose and solid preparation |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP2000327701A (en) |
| KR (1) | KR20010029723A (en) |
| CN (1) | CN1203896C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6700083B2 (en) * | 2016-03-30 | 2020-05-27 | 株式会社ファンケル | Orally fast disintegrating tablets |
| JP6700084B2 (en) * | 2016-03-30 | 2020-05-27 | 株式会社ファンケル | Coated granules |
| WO2018021265A1 (en) | 2016-07-27 | 2018-02-01 | 沢井製薬株式会社 | Additive composition for orally disintegrating tablet |
| JP6651638B2 (en) | 2016-09-06 | 2020-02-19 | 沢井製薬株式会社 | Orally disintegrating tablet additive composition |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61100519A (en) * | 1984-10-23 | 1986-05-19 | Shin Etsu Chem Co Ltd | Hard capsule for drug |
| JP2602535B2 (en) * | 1988-09-02 | 1997-04-23 | ダイセル化学工業株式会社 | Aminoethylated water-soluble polymer and its production method |
| DE19504832A1 (en) * | 1995-02-14 | 1996-08-22 | Basf Ag | Solid drug preparations |
| JP3947244B2 (en) * | 1996-04-04 | 2007-07-18 | 日清ファルマ株式会社 | Preparation for peptic ulcer treatment |
| JP3572213B2 (en) * | 1999-01-18 | 2004-09-29 | 信越化学工業株式会社 | Low substituted hydroxypropylcellulose |
-
1999
- 1999-05-18 JP JP11136788A patent/JP2000327701A/en active Pending
-
2000
- 2000-05-17 KR KR1020000026310A patent/KR20010029723A/en not_active Application Discontinuation
- 2000-05-18 CN CNB001085816A patent/CN1203896C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| KR20010029723A (en) | 2001-04-16 |
| JP2000327701A (en) | 2000-11-28 |
| CN1203896C (en) | 2005-06-01 |
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Granted publication date: 20050601 Termination date: 20190518 |