CN1552324A - Medicinal composition for stabilizing delotadine in preparation - Google Patents
Medicinal composition for stabilizing delotadine in preparation Download PDFInfo
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- CN1552324A CN1552324A CNA031299377A CN03129937A CN1552324A CN 1552324 A CN1552324 A CN 1552324A CN A031299377 A CNA031299377 A CN A031299377A CN 03129937 A CN03129937 A CN 03129937A CN 1552324 A CN1552324 A CN 1552324A
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- pharmaceutical composition
- antioxidant
- desloratadine
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Abstract
A composite medicine in which desloratadine is stabilized features that after desloratadine is mixed with medicinal auxiliaries, an antioxidizing agent is added to the mixture.
Description
Technical field
The present invention relates to a kind of antihistaminic 8-chloro-6 that makes, 11-dihydro-11-(4-piperidylidene)-5H-benzo [1,2-b] pyridine promptly is called desloratadine (DCL) stable pharmaceutical composition in preparation.
Background technology
Desloratadine (DCL) is the active metabolite of loratadine (loratadine), is the non-sedating antihistaminic, and the side effect of no maincenter and nervous system aspect is as drowsiness and cholinolytic effect, as histamine H
1Receptor antagonist, zoopery show DCL antagonism H
1The effect of receptor is 2.5～4 times of loratadine, thereby the dose minimizing, and side effect is slighter.The of paramount importance DCL of being shows a kind of congestion effect when treatment seasonality, allergic rhinitis, this point is different from other antihistaminic of great majority, what the specific activity loratadine of report DCL in tumor enhancement arranged simultaneously hangs down 5 to 7 times, therefore compare with loratadine, desloratadine (DCL) effect is stronger, and safety is better.
In the CN 98802313.X patent, disclose the preparation prescription of desloratadine, lay special stress on DCL instability can not contain especially lactose of monosaccharide and disaccharide under the prerequisite that has water to exist, otherwise the stability of drug extreme difference.Main cause is that lactose and DCL can form a kind of brown product, makes the DCL degraded generate a kind of brown alkene ammoniacal substance, causes DCL highly to degrade, and influences its stability in compositions.The method that proposes to solve has two kinds (1) not use especially lactose of monosaccharide or disaccharide in the pharmaceutical composition of desloratadine (DCL); (2) even must use, the mode that can take on the one hand desloratadine and monosaccharide or disaccharide, especially lactose are completely cut off is promptly at first with the desloratadine coating or after making microcapsule, again with the blended mode of lactose.Also can take the anhydrous mode of strict control on the other hand.Under these two kinds of conditions, desloratadine mixes also with lactose can keep its stability.
Well-known lactose all is the chemical compound of using always of making filler in tablet, capsule, the granule for example at many pharmaceutical dosage forms, has good flowability and compressibility.So,, can bring inconvenience to large-scale industrial production, and influence the quality of medicine if in the pharmaceutical composition prescription, do not use especially lactose of monosaccharide and disaccharide.Adopt isolation coat in addition or make the stability that microcapsule also just partly increases raw material, and complex operation, cost is higher.In addition, in process of the test, contain especially lactose of monosaccharide and disaccharide even we find not add in preparation prescription, made preparation also can produce a kind of brownish red material, is difficult to long preservation.
CN 02128998.0 also discloses another and has made desloratadine (DCL) stable preparation method in preparation, mainly be the amino and corresponding organic acid or inorganic acid reaction that utilizes in the DCL molecule, generate Water Soluble Compound salt, thereby increased the dissolubility of DCL, but the method at first needs DCL and sour salify after numerous and diverse technical processs such as decolouring, concentrated, precipitation and crystallization are prepared into pure product, be mixed and made into various dosage forms with pharmaceutic adjuvants such as lactose again, this has increased the synthesis technique of crude drug undoubtedly.
Summary of the invention
Purpose of the present invention is intended to overcome the shortcoming and defect of above-mentioned prior art, and a kind of easy, unique method is provided, and can make antihistaminic desloratadine (DCL) stable pharmaceutical composition in preparation.
The object of the present invention is achieved like this: the desloratadine that will treat effective dose joins and makes multiple dosage form in the antioxidant with after pharmaceutic adjuvant mixes.Its dosage form can exist with the form of tablet, capsule, syrup, granule, oral liquid, dispersible tablet, fast disintegrating tablet; Wherein used antioxidant is the antioxidant that contains inorganic sulfur or organic sulfur; Inorganic sulfur antioxidant is sulphite, as sodium sulfite, potassium sulfite, sodium pyrosulfite, sodium thiosulfate, sodium sulfite, Potassium acid sulfite; Organic sulfur antioxidant is thioglycerol, thiourea, 2 mercapto ethanol, 2-mercaprol, 1-Thiosorbitol; Antioxidant of the present invention must pharmaceutically allow, and itself not biologically active or pharmacologically active, can guarantee that desloratadine contained in the preparation is not damaged, so the drug effect of desloratadine and bioavailability can not be affected; The consumption of antioxidant of the present invention is meant in the supplementary product consumption scope of stipulating in pharmacopeia, determines that through experimental study the antioxidant of adding by weight and the percentage by weight of pharmaceutical composition are 0.001%-2%, and the best is 0.017-1%.
Since have in the molecular structure of desloratadine one exposed amino, its with active hydrogen be easy to oxidation by air, cause color burn.Various experimental studies show, add an amount of antioxidant in containing the preparation prescription of desloratadine, can solve under the condition that lactose or water are arranged in prescription the desloratadine problem of unstable.The inventor finds in that the desloratadine in the preparation that adds antioxidant is made full wavelength scanner, at 245 ± 2nm place absorption maximum is arranged under study for action, and there is minimal absorption at 229.6 ± 2nm place, and is consistent with the desloratadine that does not add antioxidant (DCL) reference substance.After adding antioxidant is described, do not influence the pharmacologically active of desloratadine (DCL), seeing Table 1 is desloratadine reference substance and the UV scanning result who contains the desloratadine of antioxidant.
Reference substance and the desloratadine UV scanning that contains antioxidant:
Instrument: Tianjin, island UV-260 ultraviolet determination instrument
Method:
Precision takes by weighing an amount of desloratadine reference substance, with 95% dissolve with ethanol, makes concentration and is the solution of 10ug/ml and make full wavelength scanner.Precision takes by weighing the sheet powder that contains antioxidant in right amount (or capsule 's content powder, granule powder), with 95% dissolve with ethanol, filters with dry filter paper, makes concentration and is the solution of 10ug/ml and make full wavelength scanner, the results are shown in Table 1:
Table 1
| Absorption maximum (nm) | Minimal absorption (nm) | |
| Reference substance | ????245.6 | ????229.2 |
| Tablet | ????245.2 | ????229.4 |
| Capsule | ????244.9 | ????229.8 |
| Granule | ????245.5 | ????230.0 |
As can be seen from Table 1, in various preparations, add the pharmaceutically active that antioxidant does not influence desloratadine.
Further specify, the desloratadine of treatment effective dose of the present invention mixes with pharmaceutic adjuvant and is meant: desloratadine (DCL) general content in preparation prescription is 0.1mg-10mg, and the best is 0.1mg-5mg;
Used pharmaceutic adjuvant comprises:
Binding agent: corn starch, gelatin, cellulose and derivant thereof (ethyl cellulose, sodium carboxymethyl cellulose) hypromellose, microcrystalline Cellulose.
Filler: calcium carbonate, calcium sulfate, calcium hydrogen phosphate, mannose, lactose.
Disintegrating agent: starch, Explotab, polyvinyl pyrrolidone
Lubricant: calcium stearate, magnesium stearate, mineral oil, hydrogenated vegetable oil.
Coating materials: hypromellose, ethyl cellulose, Polyethylene Glycol.
The invention still further relates to and make desloratadine stable other treatment component in preparation, as antiseptic, correctives, sweeting agent, plasticizer etc., this treatment component joins in tablet, capsule, syrup, granule, oral liquid, dispersible tablet, the fast disintegrating tablet with a certain amount of.But what should point out is that these components must be complementary to guarantee stability of formulation with DCL.
The desloratadine of treatment effective dose mixes with an amount of antioxidant, and adding diluent, binding agent, disintegrating agent, fluidizer, lubricant be through mixing granulation, makes tablet behind the tabletting (but coating) in case of necessity; Adding diluent, disintegrating agent, lubricant, fluidizer, binding agent are made capsule, granule, dry syrup through mixing, granulation, fill; Add suitable technologies such as sweeting agent, correctives, water and make oral liquid.Desloratadine is stable in various preparations, does not produce brown materials.
The present invention is from technical standpoint, and having significantly with existing technology, different its advantages are:
1. solved desloratadine with simple, unique mode and in preparation prescription, added and contain the defective that monosaccharide and disaccharide especially produce the brownish red material under the condition of lactose, made the desloratadine in various dosage forms, all can keep its stability.
2. do not change the desloratadine structure, shortened the crude drug synthetic route, only need in adjuvant, to add an amount of antioxidant and can reach the stable purpose of desloratadine.
3. adopt the present invention to simplify operation, saved cost, be fit to large-scale industrial production more.
The specific embodiment
Below describe different embodiments in detail by various preparation prescriptions, these embodiment and do not produce any restriction to the present invention only as an illustration.
The content of desloratadine is generally 0.1-5mg in various dosage forms.Wherein the q.s representative is an amount of.
Example 1:
| Title | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 |
| Desloratadine | ????5g | ????5g | ????5g | ????5g |
| Lactose | ????30g | ????30g | ??----- | ???----- |
| Calcium hydrogen phosphate | ???----- | ???----- | ????30g | ????30g |
| Microcrystalline Cellulose | ????15g | ????15g | ????15g | ????15g |
| Starch | ????30g | ????30g | ????30g | ????30g |
| Carboxymethyl starch sodium | ????10g | ????10g | ????10g | ????10g |
| 30% ethanol | ????q.s | ????q.s | ????q.s | ????q.s |
| Sodium pyrosulfite | ???----- | ????0.05g | ???----- | ????0.05g |
| Magnesium stearate | ????q.s | ????q.s | ????q.s | ????q.s |
Make 1000
Preparation technology:
(1) plain blade technolgy:
Supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Earlier with the abundant mixing of the adjuvant of recipe quantity.Crude drug is added in the adjuvant to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of adjuvant.30% ethanol that will contain an amount of sodium pyrosulfite joins and makes soft material in the compound, crosses 20 mesh sieves, and dry 2h in 55 ℃ of ventilated drying ovens, dried granule cross the arrangement of 16 mesh sieves, measure intermediate content, tabletting.
(2) film-coat technology
Recipe quantity Opadry (coating materials) is dissolved in 70% the pure water, fully mixing.Plain sheet is placed coating pan, start air blast, making the sheet temperature is about 40 ℃, sprays into film-coat with spray gun, and spray speed is 5ml/min, sprayed to film-coat, and dry 1h, packing gets final product.
Dirt content test adopts the high performance liquid chromatogram method.
Instrument: SP8810 pump
The SP100 detector
ODSC
18Post
Embodiment 1 stability experiment result of study:
| Outward appearance | Impurity content (%) | |||
| 0 day | 5 days | 10 days | ||
| Prescription 1 | Unilateral is brownish red | 0.27 | ?0.58 | ?1.12 |
| Prescription 2 | Unilateral is off-white color | 0.28 | ?0.30 | ?0.33 |
| Prescription 3 | Unilateral is brownish red | 0.25 | ?0.47 | ?0.92 |
| Prescription 4 | Unilateral is off-white color | 0.25 | ?0.29 | ?0.30 |
Example 2
| Title | Prescription 5 | Title | Prescription 6 | Title | Prescription 7 |
| Desloratadine | 5g | Desloratadine | 5g | Desloratadine | 5g |
| Lactose | 30g | Lactose | 30g | Lactose | 30g |
| Microcrystalline Cellulose | 15g | Microcrystalline Cellulose | 15g | Microcrystalline Cellulose | 15g |
| Starch | 30g | Starch | 30g | Starch | 30g |
| Carboxymethyl starch sodium | 10g | Carboxymethyl starch sodium | 10g | Carboxymethyl starch sodium | 10g |
| 30% ethanol | q.s | 30% ethanol | q.s | 30% ethanol | q.s |
| Sodium pyrosulfite | 0.10g | Sodium sulfite | 0.10g | Sodium thiosulfate | 0.10g |
| Magnesium stearate | q.s | Magnesium stearate | q.s | Magnesium stearate | q.s |
Make 1000
Plain sheet and coating preparation technology are with example 1.
Embodiment 2 stability experiment results of study:
| Outward appearance | Impurity content (%) | |||
| 0 day | 5 days | 10 days | ||
| Prescription 5 | Unilateral is off-white color | ??0.27 | ??0.28 | ??0.29 |
| Prescription 6 | Unilateral is off-white color | ??0.28 | ??0.30 | ??0.31 |
| Prescription 7 | Unilateral is off-white color | ??0.25 | ??0.28 | ??0.29 |
Example 3
| Title | Prescription 8 | Title | Prescription 9 | Title | Prescription 10 |
| Desloratadine | 5g | Desloratadine | 5g | Desloratadine | 5g |
| Lactose | 30g | Lactose | 30g | Lactose | 30g |
| Microcrystalline Cellulose | 15g | Microcrystalline Cellulose | 15g | Microcrystalline Cellulose | 15g |
| Starch | 30g | Starch | 30g | Starch | 30g |
| Carboxymethyl starch sodium | 10g | Carboxymethyl starch sodium | 10g | Carboxymethyl starch sodium | 10g |
| 30% ethanol | q.s | 30% ethanol | q.s | 30% ethanol | q.s |
| Sodium pyrosulfite | 0.08g | Thioglycerol | 0.17g | 2 mercapto ethanol | 0.5g |
| Magnesium stearate | q.s | Magnesium stearate | q.s | Magnesium stearate | q.s |
Make 1000
Plain sheet and coating preparation technology are with example 1.
Embodiment 3 stability experiment results of study:
| Outward appearance | Impurity content (%) | |||
| 0 day | 5 days | 10 days | ||
| Prescription 8 | Unilateral is off-white color | ??0.24 | ??0.28 | ??0.31 |
| Prescription 9 | Unilateral is off-white color | ??0.28 | ??0.31 | ??0.33 |
| Prescription 10 | Unilateral is off-white color | ??0.25 | ??0.27 | ??0.29 |
Example 4
A, granule
| Title | |
| Desloratadine | ????5g |
| Sucrose | ????200g |
| Lactose | ????250g |
| Aspartame | ????35g |
| Fructus Citri tangerinae essence | ????10g |
| Sodium pyrosulfite | ????0.5g |
| 30% ethanol | ????q.s |
Make 1000 bags
Granule preparation technology:
Supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Earlier with the abundant mixing of the adjuvant of recipe quantity.Crude drug is added in the adjuvant to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of adjuvant.30% ethanol that will contain an amount of sodium pyrosulfite joins and makes soft material in the compound, crosses 20 mesh sieves, and dry 2h in 55 ℃ of ventilated drying ovens, dried granule cross the arrangement of 16 mesh sieves, measure intermediate content, and fill becomes bag.
B, capsule
| Title | |
| Desloratadine | ????5g |
| Calcium hydrogen phosphate | ????40g |
| Microcrystalline Cellulose | ????10g |
| Carboxymethyl starch sodium | ????10g |
| Thioglycerol | ????0.75g |
| Magnesium stearate | ????8g |
| 30% ethanol | ????q.s |
Make 1000
Capsule preparation technology:
Supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Earlier with the abundant mixing of the adjuvant of recipe quantity.Crude drug is added in the adjuvant to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of adjuvant.30% ethanol that will contain an amount of thioglycerol joins and makes soft material in the compound, crosses 20 mesh sieves, and dry 2h in 55 ℃ of ventilated drying ovens, dried granule cross the arrangement of 16 mesh sieves, measure intermediate content, and fill becomes capsule.
C, oral liquid
| Title | |
| Desloratadine | ????5g |
| Aspartame | ????20g |
| Essence | ????2g |
| Sodium pyrosulfite | ????5g |
| Add the injection water extremely | ????5000ml |
Make 1000 bottles
Oral liquid preparation technology:
It is standby that supplementary material is crossed 100 mesh sieves.Measure 1000ml water for injection earlier, desloratadine is under agitation dissolved (80 ℃ of water-baths in case of necessity), add the abundant stirring and evenly mixing of remaining adjuvant, and add the injection water to 5000ml, make and make transparent clarifying liquid, fill becomes bottle.
Contain in the various preparations of antioxidant the impurity content of desloratadine under 60 ℃ of conditions of high temperature.
| Outward appearance | Impurity content (%) | |||
| 0 day | 5 days | 10 days | ||
| Tablet | Unilateral is white or off-white color | ??0.24 | ??0.26 | ??0.28 |
| Capsule | Remove capsule shells, content is white or off-white color | ??0.28 | ??0.28 | ??0.31 |
| Granule | Granule is a white group white | ??0.26 | ??0.29 | ??0.32 |
| Oral liquid | Be clear solution, invariant color | ??0.30 | ??0.33 | ??0.34 |
Claims (10)
1, a kind of desloratadine stable pharmaceutical composition in preparation that makes is characterized in that the desloratadine of treatment effective dose joining and making multiple dosage form in the antioxidant with after pharmaceutic adjuvant mixes.
2, pharmaceutical composition according to claim 1, the desloratadine that it is characterized in that described treatment effective dose is 0.1-5mg.
3, pharmaceutical composition according to claim 1 is characterized in that described antioxidant is the antioxidant that contains inorganic sulfur or organic sulfur.
4,, it is characterized in that described inorganic sulfur antioxidant is sulphite according to the described pharmaceutical composition of claim 3.
5, pharmaceutical composition according to claim 3 is characterized in that described organic sulfur antioxidant is thioglycerol, thiourea, 2 mercapto ethanol, 2-mercaprol, 1-Thiosorbitol.
6, pharmaceutical composition according to claim 4 is characterized in that described sulphite is sodium sulfite, potassium sulfite, sodium pyrosulfite, sodium thiosulfate, sodium sulfite, Potassium acid sulfite.
7, pharmaceutical composition according to claim 1 is characterized in that antioxidant in preparation, not biologically active or pharmaceutically active.
8, pharmaceutical composition according to claim 1 is characterized in that the antioxidant that adds by weight and the percentage by weight of pharmaceutical composition are 0.001%-2%.
9, pharmaceutical composition according to claim 1 is characterized in that the percentage by weight of the antioxidant that adds by weight and pharmaceutical composition is best and is 0.017-1%.
10, pharmaceutical composition according to claim 1, it is characterized in that described dosage form be with tablet, capsule, syrup, granule, oral liquid, dispersible tablet, fast disintegrating tablet, form exist.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03129937 CN1245975C (en) | 2003-05-28 | 2003-05-28 | Medicinal composition for stabilizing delotadine in preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03129937 CN1245975C (en) | 2003-05-28 | 2003-05-28 | Medicinal composition for stabilizing delotadine in preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1552324A true CN1552324A (en) | 2004-12-08 |
| CN1245975C CN1245975C (en) | 2006-03-22 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03129937 Expired - Fee Related CN1245975C (en) | 2003-05-28 | 2003-05-28 | Medicinal composition for stabilizing delotadine in preparation |
Country Status (1)
| Country | Link |
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| CN (1) | CN1245975C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005065047A2 (en) * | 2003-12-23 | 2005-07-21 | Sun Pharmaceutical Industries Limited | Stable oral composition containing desloratadine |
| EP1833461A1 (en) | 2004-12-22 | 2007-09-19 | Schering Corporation | Pharmaceutical formulations |
| EP2269586A1 (en) | 2009-07-01 | 2011-01-05 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Pharmaceutical composition comprising desloratadine |
| CN101548959B (en) * | 2008-04-03 | 2012-11-21 | 万特制药(海南)有限公司 | Coated tablet containing desloratadine and preparation method thereof |
| CN110840833A (en) * | 2019-11-22 | 2020-02-28 | 南京知和医药科技有限公司 | Sugar-free desloratadine oral solution and preparation process thereof |
-
2003
- 2003-05-28 CN CN 03129937 patent/CN1245975C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005065047A2 (en) * | 2003-12-23 | 2005-07-21 | Sun Pharmaceutical Industries Limited | Stable oral composition containing desloratadine |
| WO2005065047A3 (en) * | 2003-12-23 | 2006-04-27 | Sun Pharmaceutical Ind Ltd | Stable oral composition containing desloratadine |
| US7955620B2 (en) | 2003-12-23 | 2011-06-07 | Sun Pharmaceutical Industries Limited | Stable oral composition |
| EP1833461A1 (en) | 2004-12-22 | 2007-09-19 | Schering Corporation | Pharmaceutical formulations |
| JP2008521939A (en) * | 2004-12-22 | 2008-06-26 | シェーリング コーポレイション | Pharmaceutical formulation |
| CN101548959B (en) * | 2008-04-03 | 2012-11-21 | 万特制药(海南)有限公司 | Coated tablet containing desloratadine and preparation method thereof |
| EP2269586A1 (en) | 2009-07-01 | 2011-01-05 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Pharmaceutical composition comprising desloratadine |
| WO2011000518A1 (en) | 2009-07-01 | 2011-01-06 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Pharmaceutical composition comprising desloratadine |
| CN110840833A (en) * | 2019-11-22 | 2020-02-28 | 南京知和医药科技有限公司 | Sugar-free desloratadine oral solution and preparation process thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1245975C (en) | 2006-03-22 |
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Address after: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee after: TIANJIN INSTITUTE OF PHARMACEUTICAL RESEARCH CO., LTD. Address before: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee before: Tianjin Institute of Pharmaceutical Research |
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