CN1167415C - Orally applied solid preparation of medicine difficult to dissolve - Google Patents
Orally applied solid preparation of medicine difficult to dissolve Download PDFInfo
- Publication number
- CN1167415C CN1167415C CNB011013354A CN01101335A CN1167415C CN 1167415 C CN1167415 C CN 1167415C CN B011013354 A CNB011013354 A CN B011013354A CN 01101335 A CN01101335 A CN 01101335A CN 1167415 C CN1167415 C CN 1167415C
- Authority
- CN
- China
- Prior art keywords
- weight
- preparation
- acid
- oral solid
- tegaserod
- 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.)
- Expired - Fee Related
Links
Abstract
The present invention relates to a low water-soluble medicine and/or an acid-sensitivity medicine, an oral solid preparation of a composition of the low water-soluble medicine and the acid-sensitivity medicine, and preparation method thereof. The preparation of the present invention is characterized in that the dosage of disintegrant accounts for less than 15% of total tablet weight. The oral solid preparation of the present invention can be used for treating and/or preventing motor function disturbance diseases of the gastrointestinal tract.
Description
The present invention relates to oral solid formulation of poorly water soluble drugs and/or acid sensitive drug and preparation method thereof.Especially the present invention relates to the oral solid formulation that tegaserod or its acid add alkali salt.
Poorly water soluble drugs and/or acid sensitive drug are when making solid orally ingestible, because disintegration time is slow, drug dissolution is low, so medicine is difficult to reach treatment required effective bioavailability and drug effect concentration.In addition, chemical degradation can take place in acid sensitive drug chance acid condition in production and storage process.PCT patent WO0010526 discloses a kind of disintegrating agent consumption and has surpassed preparation of solid orally ingestible such as tablet total weight amount 15 weight % (weight % refers to percentage by weight) and preparation method thereof, and the oral solid formulation that the document is put down in writing can make poorly water soluble drugs and/or acid sensitive drug reach the requirement of dissolution.But because of disintegrating agent consumption excessive (nearly 40 weight %), cause the oral solid formulation hygroscopicity strong in said preparation and the preparation method, poor stability, the cost height is unfavorable for large-scale industrial production and storage.
The objective of the invention is to develop oral solid formulation new and poorly water soluble drugs that be suitable for large-scale industrial production and/or acid sensitive drug.
The inventor passes through research extensively and profoundly, now unexpectedly find, solid orally ingestible as shipwreck soluble drug and/or acid-sensitive sense medicine contains the disintegrating agent that is lower than 15 weight %, be lower than binding agent and an amount of cosolvent and the lubricant of 1 weight %, can make the very fast stripping in neutral solvent such as pure water of poorly water soluble drugs and/or acid sensitive drug, and reach the dissolution requirement of pharmacopeia regulation, can improve simultaneously poorly water soluble drugs and/or acid sensitive drug oral solid formulation stability and to the sensitivity of acid, make it that chemical degradation not take place.Above-mentioned new solid orally ingestible also greatly reduces production cost, thereby can carry out large-scale industrial production and storage.
First aspect present invention relates to a kind of long-term stability, hygroscopicity is low, active constituents of medicine stripping property high good poorly water soluble drugs and/or acid sensitive drug oral solid formulation, and it is characterized in that: said preparation contains the disintegrating agent that is lower than 15 weight %.
The method of the oral solid formulation of another aspect of the present invention a kind of simple and suitable large-scale industrial production poorly water soluble drugs and/or acid sensitive drug, this method comprises poorly water soluble drugs and/or acid sensitive drug and is lower than the disintegrating agent of 15 weight %, 30-90 weight % diluent, binding agent and cosolvent and mix lubricant.
Term in the present invention, " poorly water soluble drugs " are meant that dissolubility at room temperature (as 25 ℃) neutral aqueous solution Chinese medicine between 0.0001 weight % to 1 weight %, is meant that especially dissolubility is lower than the medicine of 0.01 weight %.
Term " acid sensitive drug " is meant under weak acid environment can be by chemical degradation less than medicine under 6 the condition as pH, is meant especially to lose in 2 hours under weakly acidic condition or change active medicine.
Preferred slightly water-soluble and/or acid sensitive drug are meant the digestive tract power medicine of slightly water-soluble and/or acid-sensitive sense according to the present invention, and preferred digestive tract power medicine is 5-HT
4Receptor stimulating agent or 5-HT
4Acceptor portion agonist, they mainly exist with the form of acid-addition salts such as maleate or hydrochlorate, also can exist with the form of free alkali.
According to the present invention, the gastrointestinal drug of particularly preferred slightly water-soluble and/or acid-sensitive sense is the acid-addition salts of tegaserod such as the inorganic acid salt example hydrochloric acid salt of tegaserod, or sulfate or phosphate, acylate such as acetate, citrate, the tegaserod maleate of maleate or tartrate etc., especially following formula (Tegaserod Maleate, 2-(5-methoxyl group-1H-indole-3-formaldehyde contract amino)-2 '-amyl group guanidine maleate):
According to the present invention, slightly water-soluble and/or sensitivity to acid active component such as tegaserod maleate preferred part by weight in solid orally ingestible is 0.2-15 weight %, and particularly preferred ratio is 2-8 weight %.
The used disintegrating agent of the present invention is meant and adds disintegrate that a kind of and/or several in solid preparation such as the tablet promote solid preparation discharges active component from preparation material to.Preferred disintegrating agent can be a crospovidone (crospovidone) as Polyplasdone XL-10
, Polyplasdone XL
, Kollidon CL
Starch; Cross-linking sodium carboxymethyl cellulose and/or their mixture.Preferred disintegrating agent accounts for the 0.1-15 weight % of solid orally ingestible weight, more preferably 8-15 weight % among the present invention.The disintegrating agent of first-selection of the present invention is a crospovidone, and particularly particle diameter is less than 80 microns crospovidone Polyplasdone XL-10
According to the present invention, oral solid formulation of the present invention is formed and is also comprised a kind of and/or multiple other excipient.Preferred other excipient comprises:
Diluent: the oral administration solid tablet must add diluent could be suppressed in flakes.For the active component of slightly water-soluble and/or sensitivity to acid, select the solubility adjuvant particularly main as diluent.Preferable absorbent can be lactose and mannitol or their mixture.First-selected diluent is the mixture of lactose and mannitol, and it is difficult for moisture absorption, has good compressibility, and is soluble in water, helps disintegration of tablet and stripping.Preferable absorbent accounts for the 30-90 weight % of solid orally ingestible weight among the present invention, and particularly preferred ratio is 65-75 weight %;
Binding agent: for slightly water-soluble and/or sensitivity to acid active component, when preparation solid orally ingestible such as tablet, the selection of binding agent is the key that guarantees the solid preparation quality, and it can make tablet have better hardness.First-selected binding agent is a hydroxypropyl emthylcellulose, and its consumption is little, and adhesion strength is strong, helps the active constituents of medicine stripping.Preferred adhesive accounts for the 0.1-1 weight % of solid orally ingestible weight, more preferably 0.5-1 weight % among the present invention;
Cosolvent: in binding agent, add non-ionic surface active agent as cosolvent, can increase the dissolution of insoluble drug, and can simplify the operation, help suitability for industrialized production.The preferred cosolvent of the present invention is a poloxamer.The weight ratio that preferred cosolvent accounts for solid orally ingestible among the present invention is 0.1-10 weight %, and particularly preferred ratio is 1-5 weight %;
Lubricant: can improve the quick stripping of insoluble drug in the solid orally ingestible, can prevent the chemical degradation of acid sensitive drug.The preferred lubricant of the present invention can be a soluble oil, as Polyethylene Glycol (PEG), sodium chloride, glyceryl monostearate or castor oil hydrogenated and hydrophobic lubricant, as magnesium stearate.The preferred lubricant of the present invention is the water-soluble polyethylene glycol of molecular weight between 1000-10000 dalton, particularly preferably is the Polyethylene Glycol of molecular weight between 4000-8000 dalton.Particularly preferably being molecular weight is 6000 daltonian Polyethylene Glycol (PEG6000), as other the hydrophobic lubricant that adds in the preparation of the present invention, preferred magnesium stearate is as hydrophobic lubricant, preferred magnesium stearate accounts for the 0.01-3 weight % of solid orally ingestible weight, preferred especially 0.1-0.15 weight %.The adding of magnesium stearate has overcome uses the sticking problem that PEG causes, and has increased particulate flowability, makes the stripping of insoluble drug unaffected simultaneously.
The solid orally ingestible particularly suitable of the present invention preparation of slightly water-soluble and/or acid sensitive drug, the preferred medicine in the preparation can be 5-HT
4Receptor stimulating agent or partial agonist, particularly preferred medicine is a tegaserod maleate.
According to a preferred embodiment of the invention, the solid orally ingestible of shipwreck soluble drug of the present invention comprises active constituents of medicine such as the tegaserod maleate of 2-8 weight %, 8-15 weight % crospovidone as disintegrating agent, 65-75 weight % lactose and mannitol (ratio is 4: 3) as diluent, 0.5-1 weight % hydroxypropyl emthylcellulose as binding agent, as the 1-5 weight % poloxamer of cosolvent, as the 1-5 weight %PEG6000 and the 0.01-3 weight % magnesium stearate of lubricant.
According to embodiment of the present invention, poorly water soluble drugs of the present invention and/or acid sensitive drug solid orally ingestible are to contain poorly water soluble drugs and/or acid sensitive drug is the oral formulations of tegaserod maleate, and it is 90-100% that the dissolution in its buffer solution between the pH6.8-7.5 of neutral aqueous solution or pharmacopeia regulation can reach 20 minutes medicine dissolution rates.
According to the present invention, 5-HT of the present invention
4The oral formulations of receptor stimulating agent or partial agonist such as tegaserod maleate can be used for treating and/or preventing gastrointestinal movement dysfunction disease, as irritable bowel trace integration disease (Irritable Bowel Syndrome, IBS), gastroesophageal reflux disease (Gastro-Esophageal Reflux Disease, GERD), functional dyspepsia (Functional Dyspepsia, FD) and postoperative ileus (Post Operative Ileus, POI).
According to the present invention, the present invention solid orally ingestible can be tablet, quick-release tablet, mouthful solvellae, slow releasing tablet, controlled release tablet, capsule such as hard capsule, quick-release capsules, slow releasing capsule or controlled release capsule etc.
The preferred embodiment of poorly water soluble drugs and/or acid sensitive drug solid orally ingestible preparation method according to the present invention, this method comprises:
With 2-8 weight % insoluble drug and/or sensitivity to acid material medicine tegaserod maleate, with 65-75 weight % lactose and mannitol (lactose 50-90 weight %, mannitol 10-50 weight %), 8-15 weight % crospovidone mixes, then the gained mixture is mixed with hydroxypropyl emthylcellulose and granulate, after gained the material drying again with the poloxamer of 1-20 weight %, polyethylene glycol 6000 and magnesium stearate mix.
According to this suction, the poorly water soluble drugs of the present invention and/or the oral solid formulation of acid sensitive drug such as tegaserod maleate tablet are pressed 2000 editions two dissolution test methods of Chinese Pharmacopoeia, check that in accordance with the law dissolution is as follows:
| 5 minutes | 30-90％ |
| 10 minutes | 60-100％ |
| 20 minutes | 90-100％ |
| 30 minutes | 95-100％ |
The following example is used to illustrate the present invention, but does not mean that the present invention is had any restriction.
Embodiment 1 contains the preparation (2 milligrams of tegaserod maleate/sheets) of slightly water-soluble acid sensitive drug-tegaserod maleate tablet
(1) preparation of binding agent
With hydroxypropyl emthylcellulose 2.5 gram, put in 100 milliliters of measuring bottles, add pure water to 90 milliliter, stir and make dissolving.Add poloxamer 8 grams again, stir and make dissolving, add adding water to capacity, mixing, make clear and bright viscous solution, filtered through gauze was with preparation in preceding 24 hours, it is standby that 2-8 ℃ of refrigerator deposited, and makes to contain hydroxypropyl emthylcellulose 2.5 grams, the solution for standby of poloxamer 8 grams in per 100 ml waters.
(2) weighing of former, adjuvant with mix
To cross tegaserod maleate 2.77 grams of 240 mesh sieves, cross lactose 53.60 grams, mannitol 40.00 gram and crospovidone (the Polyplasdone XL-10 of 100 mesh sieves
) 17.66 grams, with the equivalent method mix homogeneously that progressively increases, and cross 40 mesh sieve secondaries, as mixed powder.
(3) granulate
Slowly add 36 milliliters of hydroxypropyl emthylcellulose binding agent, poloxamer 2.88 grams that contain 0.9 gram in mixed powder, the limit edged stirs, and makes soft material, granulates twice through 20 mesh sieves.Wet grain is put 65-70 ℃ of timely aeration-drying, and dried granule adds 200 order polyethylene glycol 6000s, 7 grams behind 20 mesh sieve granulate, behind the mixing, adds 100 order magnesium stearates, 0.19 gram again, mixing.
(4) tabletting
The granule of making is in time used 7 millimeters scrobicula stampings of diameter, regulates pressure 3.5-6 kilogram simultaneously, and every sheet weighs 125 milligrams.
The composition of embodiment 2 tegaserod maleate tablet preparations (2 milligrams of tegaserod maleate/sheets)
| Composition | Per 1000 consumptions (gram) |
| Tegaserod maleate | 2.77 |
| Lactose | 53.60 |
| Mannitol | 40.00 |
| Crospovidone | 17.66 |
| Hydroxypropyl emthylcellulose | 0.90 |
| Poloxamer | 2.88 |
| Polyethylene glycol 6000 | 7.00 |
| Magnesium stearate | 0.19 |
| Full dose | 125 grams |
Embodiment 3 contains the preparation (6 milligrams of tegaserod/sheets) of tegaserod maleate tablet
(1) preparation of binding agent
With hydroxypropyl emthylcellulose 2.5 gram, put in 100 milliliters of measuring bottles, add pure water to 90 milliliter, stir and make dissolving.Add poloxamer 8 grams again, stir and make dissolving, add adding water to capacity, mixing, make clear and bright viscous solution, filtered through gauze was with preparation in preceding 24 hours, it is standby that 2-8 ℃ of refrigerator deposited, and makes to contain hydroxypropyl emthylcellulose 2.5 grams, the solution for standby of poloxamer 8 grams in per 100 ml waters.
(2) weighing of former, adjuvant with mix
To cross tegaserod maleate 8.31 grams of 240 mesh sieves, cross lactose 50.00 grams, mannitol 38.00 gram and the crospovidone (PolyplasdoneXL-10 of 100 mesh sieves
) 17.72 grams, with the equivalent method mix homogeneously that progressively increases, and cross 40 mesh sieve secondaries, as mixed powder.
(3) granulate
Slowly add 36 milliliters of hydroxypropyl emthylcellulose binding agent, poloxamer 2.88 grams that contain 0.9 gram in mixed powder, the limit edged stirs, and makes soft material, granulates twice through 20 mesh sieves.Wet grain is put 65-70 ℃ of timely aeration-drying, and dried granule adds 200 order polyethylene glycol 6000s, 7 grams behind 20 mesh sieve granulate, behind the mixing, adds 100 order magnesium stearates, 0.19 gram again, mixing.
(4) tabletting
The granule of making is in time used 7 millimeters scrobicula stampings of diameter, regulates pressure 3.5-6 kilogram simultaneously, and every sheet weighs 125 milligrams.
Embodiment 4 tegaserod maleate tablet preparations are formed (6 milligrams of tegaserod maleate/sheets)
| Composition | Per 1000 consumptions (gram) |
| Tegaserod maleate | 8.31 |
| Lactose | 50.00 |
| Mannitol | 38.00 |
| Crospovidone | 17.72 |
| Hydroxypropyl emthylcellulose | 0.90 |
| Poloxamer | 2.88 |
| Polyethylene glycol 6000 | 7.00 |
| Magnesium stearate | 0.19 |
| Full dose | 125 grams |
The test of embodiment 5 tegaserod maleate tablet dissolutions
Press 2000 editions two dissolution test methods of Chinese Pharmacopoeia, measure the dissolution in the tegaserod maleate tablet 30 minutes of embodiment 2 and 4, leaching condition is for being dissolution medium with the pure water in accordance with the law, 50 rpms of rotating speeds, 37 degrees centigrade of temperature, the percentage dissolution rate is as shown in the table.
The percentage dissolution rate (%) of tegaserod maleate sheet different time
| Time (minute) | 5 | 10 | 20 | 30 |
| Embodiment 2 tablet dissolution rates (%) | 42.2 | 65.1 | 94.8 | 97.3 |
| Embodiment 4 tablet dissolution rates (%) | 49.9 | 83.7 | 98.3 | 99.8 |
Claims (6)
1. the oral solid formulation that contains tegaserod or its acid-addition salts, it contains the tegaserod of 0.2-15 weight % or its acid with salt, 0.1-15 weight % is selected from crospovidone, starch, the disintegrating agent of cross-linking sodium carboxymethyl cellulose or their mixture, 0.1-1 weight % is selected from the binding agent of hydroxypropyl emthylcellulose, 30-90 weight % is selected from lactose, the diluent of mannitol or their mixture, 1-5 weight % is selected from the cosolvent of poloxamer, 1-5 weight % is selected from Polyethylene Glycol, and sodium chloride, glyceryl monostearate or hydrogenation castor drench the hydrophilic lubricant of oil and the hydrophobic lubricant that 0.01-3 weight % is selected from magnesium stearate.
2. the oral solid formulation of claim 1, wherein disintegrating agent is the crospovidone that accounts for the heavy 0.1-15% of preparation, diluent is to account for the lactose of the heavy 65-75% of preparation and the mixture of mannitol, and hydrophilic lubricant is the daltonian Polyethylene Glycol of 1000-10000 for accounting for heavy 1-5% of preparation and molecular weight.
3. claim 1 or 2 oral solid formulation, wherein the tegaserod acid-addition salts is a tegaserod maleate.
4. the oral solid formulation of claim 3, wherein disintegrating agent is a crospovidone, diluent is the mixture of lactose and mannitol, binding agent is a hydroxypropyl emthylcellulose, cosolvent is a poloxamer, and hydrophilic lubricant is PEG6000, and hydrophobic lubricant is a magnesium stearate.
5. the oral solid formulation of claim 4, wherein said preparation are that tablet and every contain the 2mg tegaserod maleate.
6. the oral solid formulation of claim 4, wherein said preparation are that tablet and every contain the 6mg tegaserod maleate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011013354A CN1167415C (en) | 2001-01-04 | 2001-01-04 | Orally applied solid preparation of medicine difficult to dissolve |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011013354A CN1167415C (en) | 2001-01-04 | 2001-01-04 | Orally applied solid preparation of medicine difficult to dissolve |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1305806A CN1305806A (en) | 2001-08-01 |
| CN1167415C true CN1167415C (en) | 2004-09-22 |
Family
ID=4652024
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB011013354A Expired - Fee Related CN1167415C (en) | 2001-01-04 | 2001-01-04 | Orally applied solid preparation of medicine difficult to dissolve |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1167415C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336096B (en) | 2018-10-19 | 2023-09-26 | 深圳市纳设智能装备有限公司 | Equipment for open type continuous growth of carbon nano material and preparation method |
-
2001
- 2001-01-04 CN CNB011013354A patent/CN1167415C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1305806A (en) | 2001-08-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4077886B2 (en) | Long-acting heterodisperse hydrogel system of insoluble drugs | |
| US9629800B2 (en) | Gastroretentive formulations and manufacturing process thereof | |
| US20070190135A1 (en) | Phosphate-binding polymer and tablets using the same | |
| RU2322978C2 (en) | Pharmaceutical compositions containing partial 5ht4 agonist | |
| CN1178659C (en) | Medicamenet formulation with a controlled release of an active agent | |
| AU2010274589A1 (en) | Oral pharmaceutical composition of rasagiline and process for preparing thereof | |
| RU2300368C2 (en) | Ibuprofen-containing composition | |
| EP1589950A1 (en) | Methods for making pharmaceutical dosage forms containing active cushioning components | |
| ES2513415T3 (en) | Pharmaceutical compositions comprising an HCV polymerase inhibitor prodrug | |
| US6372259B1 (en) | Palatable, sustained release drug granules | |
| JP2009519313A (en) | Pharmaceutical composition | |
| CN1167415C (en) | Orally applied solid preparation of medicine difficult to dissolve | |
| CA2812665C (en) | Pharmaceutical composition for treating hcv infections | |
| WO2008145361A1 (en) | Mineral-fiber solid dispersion, method for preparing the same, and use thereof as pharmaceutical tableting aid | |
| KR20210003323A (en) | Pharmaceutical compositions including tamsulosin or its hydrochloride salt and preparation method thereof | |
| KR20180035723A (en) | Controlled release formulation for administration of Lacosamide | |
| JP2008530080A (en) | Ocaperidone-containing composition | |
| CN1798562A (en) | Composition for oral administration containing itraconazole | |
| CN101152142A (en) | Solid pharmaceutical composition containing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-5-thiazole methanoic acid | |
| WO2021126099A1 (en) | An enteric coated pellet comprising duloxetine hydrochloride with optimized degrees of neutralization | |
| WO2023080855A1 (en) | Pharmaceutical composition comprising mirabegron and calcium salts | |
| WO2022115054A1 (en) | Enteric coated duloxetine compositions | |
| KR100874401B1 (en) | Itraconazole-containing solid dispersion and preparation method thereof | |
| CN1166364C (en) | Controlled drug delivery system for diltiazem | |
| CN1615825A (en) | Poly unit slow release preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C06 | Publication | ||
| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040922 Termination date: 20200104 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |