CN1680427A - Water soluble piduomode composite salt and its preparation - Google Patents
Water soluble piduomode composite salt and its preparation Download PDFInfo
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- CN1680427A CN1680427A CN 200510009242 CN200510009242A CN1680427A CN 1680427 A CN1680427 A CN 1680427A CN 200510009242 CN200510009242 CN 200510009242 CN 200510009242 A CN200510009242 A CN 200510009242A CN 1680427 A CN1680427 A CN 1680427A
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- pidotimod
- salt
- meglumine
- arginine
- preparation
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Abstract
Water soluble Piridomode double salt and its production are disclosed. It is carried out by mixing Piridomode with arginine, lysine and glucomethylamine in solvent, contacting in liquid environment, forming double salt, removing solvent, and using safe alkali compound as double ligand. It achieves form of water soluble compound and more convenient.
Description
Technical field
The invention belongs to medical technical field, relate to compound salt of a kind of immunopotentiating agent class medicine pidotimod and preparation method thereof, this pidotimod double salt has water-soluble preferably.
Background technology
Immune response is present in the generation and evolution of many diseases, all easily cause in various degree immune deficiency as bacterial infection disease, tumour, viral infection, liver or renal insufficiency and other chronic wasting disease (as chronic hepatitis, chronic bronchitis etc.), and immune deficiency can increase the weight of the state of an illness and forms vicious cycle.
Pidotimod (pidotimod) chemical name is: (R)-3-[(S)-(5-oxo-2-pyrrolidyl) carbonyl]-tetrahydro-thiazoles-4-carboxylic acid, molecular structural formula is as follows
The poorly water-soluble of pidotimod, and content is also bigger in the unit formulation of its medicine, generally be to contain 0.4 gram pidotimod in the per unit preparation (as every, every bag granule, every bottle of oral liquid, every bottle of injection etc.), this need add a large amount of solubility promoters and pH value conditioning agent when just making the pharmaceutical preparation for preparing pidotimod, quality and safety for pharmaceutical preparation have bigger influence, and poorly water-soluble has also influenced the bio-absorbable availability and the curative effect of pidotimod.
The objective of the invention is provides a kind of good water solubility, pH value of water solution acidity double salt chemical combination near the minimum pidotimod of neutrality and toxic side effect and preparation method thereof at the problems referred to above.
Summary of the invention
Contain in the molecular structure of pidotimod carboxyl (COOH), be acidic-group, involved in the present invention its be pidotimod and have the formed double salt of better water miscible basic cpd, with and preparation method thereof.
Of the present invention have better water miscible basic cpd and comprise arginine, Methionin, meglumine, these three kinds of compounds are alkalescence in the aqueous solution, be easy to form double salt soluble in water with pidotimod, the compound salt that they and pidotimod form is respectively pidotimod arginine salt, pidotimod lysine salt, pidotimod meglumine salt.
The arginine chemical name is 2-amino-5-guanidine radicals valeric acid, is a kind of basic aminoacids of safety non-toxic, is the optically active form structure, its levo form structure commonly used on the pharmacology, and the molecular structural formula of pidotimod arginine salt is as follows:
Molecular formula is: [C
9H
12N
2O
4S] .a[C
6H
14N
4O
2], wherein a is and the salifiable arginic molecule number of pidotimod, that is the ratio of two active centre arginine and the mole number of pidotimod in the pidotimod arginine salt, the span of a is 0.1～20, and the value of a can be a decimal, also can be integer, in the preparation, control pidotimod and the arginic reacting weight that feeds intake, the value difference of may command a makes the pidotimod arginine salt of different salify ratios.
Especially, pidotimod and arginine be with 1: 1 molecule number proportioning salify, i.e. one-tenth salt form during a=1, and at this moment its molecular structural formula is as follows:
The Methionin chemical name is 2, and the 6-diaminocaproic acid is a kind of basic aminoacids of safety non-toxic, is the optically active form structure, its levo form structure commonly used on the pharmacology, and the molecular structural formula of pidotimod lysine salt is as follows:
Molecular formula is: [C
9H
12N
2O
4S] .a[C
6H
14N
2O
2], wherein a is the molecule number with the salifiable Methionin of pidotimod, that is the ratio of two active centre Methionin and the mole number of pidotimod in the pidotimod lysine salt, the span of a is 0.1～20, and the value of a can be a decimal, also can be integer, in the preparation, the reacting weight that feeds intake of control pidotimod and Methionin, the value difference of may command a makes the pidotimod lysine salt of different salify ratios.
Especially, pidotimod and Methionin is with 1: 1 molecule number proportioning salify, i.e. one-tenth salt form during a=1, and at this moment its molecular structural formula is as follows:
The meglumine chemical name is 1-deoxidation-1-(methylamino-)-D-sorbyl alcohol, molecular formula C
7H
17NO
5, have basic group in the meglumine molecule, be a kind of free alkali compounds of safety non-toxic, in medicine industry, be commonly used for solubility promoter, its aqueous solution is alkalescence, and the molecular structural formula of pidotimod meglumine salt is as follows:
Especially, pidotimod and meglumine be with 1: 1 molecule number proportioning salify, i.e. one-tenth salt form during a=1, and at this moment its molecular structural formula is as follows:
The invention provides the compound salt of three kinds of pidotimods, be acidic-group and the arginine that utilizes pidotimod, the compound salt that carries out acid-base reaction between the basic group of Methionin or meglumine and form, its preparation method is with pidotimod and arginine, Methionin or meglumine be thorough mixing in suitable solvent, make pidotimod and arginine, Methionin or meglumine contact in liquid environment and form double salt, again solvent is passed through evaporation, filter, oven dry or method such as lyophilize and remove promptly can obtain the arginine of the pidotimod of solid form, Methionin or meglumine double salt.During preparation, regulate and control the reacting weight that feeds intake of pidotimod and arginine, Methionin or meglumine, can make the double salt of different salify ratios.
In addition, what those of skill in the art of the present invention were appreciated that is that pidotimod and arginine, Methionin or meglumine are in the salify preparation process, in order to keep distinctive crystalline structure, can contain crystal water, therefore, the double salt of pidotimod of the present invention also comprises its crystalline hydrate.
The compound salt of pidotimod of the present invention has and the on all four pharmacological action of pidotimod, because it has well water-soluble, with the basic cpd of safety as the double salt ligand, for the application of pidotimod on medicine provides new water-soluble (water solubility is greater than 30%) compound form, be used to prepare medicament and use more convenient, adopt appropriate pharmaceutical excipient and preparation method, can make acceptable pharmaceutical dosage form on any medicine, for example powder injection, the injection liquid of injection use; Tablet for oral use, oral liquid, granule, or the like.
Embodiment
Come the double salt of pidotimod of the present invention done further specifying by the following examples, but do not represent the embodiment limitation of the present invention.
The preparation of embodiment 1. pidotimod arginine salts (1: 1)
Getting pidotimod 0.50g (about 0.002mol) adds the 3ml dehydrated alcohol and is modulated into suspension, after other gets L-arginine 0.35g (about 0.002mol) and adds the 2ml water dissolution, under the room temperature L-arginine solution is slowly dropped in the suspension of pidotimod, add fully follow-up persistent oscillation shake up mixed solution is dissolved fully be clear and bright state after, in solution, add the 12ml dehydrated alcohol again and the turbid liquid of oyster white promptly occurs, this emulsion is put the freezing liquid of crossing of refrigerator makes its post precipitation remove supernatant liquid, with throw out vacuum-drying to constant weight, obtain crystalline powder, with dehydrated alcohol rinsing 2～3 times, filter also and promptly get pidotimod arginine, molecular formula C behind the pressure reducing and steaming dehydrated alcohol
9H
12N
2O
4S.C
6H
14N
4O
2, the crystalline powder that is white in color, yield about 92.2%.
The preparation of embodiment 2. pidotimod lysine salts (1: 1)
Get and add pidotimod 5.0g (about 0.02mol) again after L-Methionin 3.0g (about 0.02mol) adds the 30ml water dissolution, fully stir mixed solution is dissolved fully be clear and bright after, smart filter, filtrate are adopted freeze-dry process that it is carried out lyophilize and are obtained the white solid state powder, are pidotimod Methionin [C
9H
12N
2O
4S.C
6H
14N
2O
2].
The preparation of embodiment 3. pidotimod meglumine salts (1: 1)
Get pidotimod 5.0g (about 0.02mol), meglumine 4.0g (about 0.02mol) and add 100ml water, stirring at room to raw material all dissolves, and spraying drying gets white powder, i.e. pidotimod meglumine, molecular formula C
9H
12N
2O
4S.C
7H
17NO
5
Embodiment four: injection pidotimod arginine lyophilized injectable powder
Prescription: pidotimod arginine 600g
N.F,USP MANNITOL 150g
Phosphate buffer is an amount of
Water for injection 2000ml
The pidotimod arginine of getting above recipe quantity dissolves with an amount of water for injection, the N.F,USP MANNITOL that adds recipe quantity again, fully pH=6～8 are regulated with phosphate buffer in the dissolving back, add needle-use activated carbon absorption pyrogen again, behind the filtering needle-use activated carbon, smart filter, after detection level is qualified, in 1000 cillin bottles of packing into filtrate branch, carry out lyophilize by lyophilized injectable powder preparation technology, can be prepared into 1000 bottles of injection pidotimod arginine lyophilized injectable powders, every bottle contains pidotimod arginine 600mg (being equivalent to pidotimod 350mg).
Embodiment five. the pidotimod lysine particle
Prescription: pidotimod Methionin 600g, sucrose 1500g, 5% polyvidone (K30) 150ml, coconut essence 0.4g pulverizes the back with the solid materials of above-mentioned recipe quantity and crosses 80 mesh sieves, mixes the back and makes softwood with povidone solution, with 12 mesh sieves granulation back oven dry, whole grain is distributed into 1000 bags, promptly gets every bag of particle that contains 600mg pidotimod Methionin.
Embodiment six. the pidotimod meglumine tablets
Prescription: pidotimod meglumine 300g, Microcrystalline Cellulose 100g, 5% polyvidone (K30) 75ml, the solid materials of above-mentioned recipe quantity is pulverized the back cross 100 mesh sieves, mix the back and make softwood, dry behind the wet granulation, whole grain with povidone solution, be pressed into 1000, promptly get every and contain 300mg pidotimod meglumine tablets.
Claims (7)
1. the compound salt of pidotimod is respectively pidotimod arginine salt, pidotimod lysine salt, pidotimod meglumine salt.
2. pidotimod arginine salt according to claim 1 is characterized in that having following molecular structural formula:
Wherein a is and the salifiable arginic molecule number of pidotimod, and the span of a is 0.1～20, preferred a=1.
3. pidotimod lysine salt according to claim 1 is characterized in that having following molecular structural formula:
Wherein a is and the molecule number of the salifiable Methionin of pidotimod, and the span of a is 0.1～20, preferred a=1.
4. pidotimod meglumine salt according to claim 1 is characterized in that having following molecular structural formula:
Wherein a is and the molecule number of the salifiable meglumine of pidotimod, and the span of a is 0.01～20, preferred a=1.
5. according to the double salt of any one described pidotimod in the claim 2 to 4, its preparation method comprises and pidotimod is contacted in suitable liquid environment with arginine, Methionin or meglumine and forms double salt, solvent is removed again.
6. according to any one is described in the claim 2 to 4, the double salt of pidotimod also comprises its crystalline hydrate.
7. according to the double salt of any one described pidotimod in the claim 2 to 4, it is characterized in that adopting appropriate pharmaceutical excipient and preparation method, can be made into acceptable pharmaceutical dosage form on any medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510009242 CN1680427B (en) | 2005-02-01 | 2005-02-01 | Water soluble piduomode composite salt and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510009242 CN1680427B (en) | 2005-02-01 | 2005-02-01 | Water soluble piduomode composite salt and its preparation |
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| Publication Number | Publication Date |
|---|---|
| CN1680427A true CN1680427A (en) | 2005-10-12 |
| CN1680427B CN1680427B (en) | 2010-08-11 |
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|---|---|---|---|
| CN 200510009242 Active CN1680427B (en) | 2005-02-01 | 2005-02-01 | Water soluble piduomode composite salt and its preparation |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105497907A (en) * | 2015-12-25 | 2016-04-20 | 夏放军 | Instant pidotimod and preparation technology thereof |
| WO2016112977A1 (en) | 2015-01-15 | 2016-07-21 | Polichem S.A. | Di-pidotimod benzathine and solid forms thereof |
| CN111214446A (en) * | 2020-03-07 | 2020-06-02 | 瑞阳制药有限公司 | Peruvir L-arginine salt freeze-dried preparation for injection |
| CN113004265A (en) * | 2019-12-19 | 2021-06-22 | 鲁南制药集团股份有限公司 | Pidotimod histidine salt crystal form and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10250081A1 (en) * | 2002-10-25 | 2004-05-13 | Boehringer Ingelheim Vetmedica Gmbh | Water-soluble meloxicam granules |
| CN1526390A (en) * | 2003-03-03 | 2004-09-08 | 浙江仙琚制药股份有限公司 | Piduomode granule and its prepn |
| CN1452960A (en) * | 2003-05-21 | 2003-11-05 | 戴建国 | Garcinolic acid injection and its prepn |
-
2005
- 2005-02-01 CN CN 200510009242 patent/CN1680427B/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016112977A1 (en) | 2015-01-15 | 2016-07-21 | Polichem S.A. | Di-pidotimod benzathine and solid forms thereof |
| WO2016113242A1 (en) * | 2015-01-15 | 2016-07-21 | Polichem S.A. | Di-pidotimod benzathine and solid forms thereof |
| CN105497907A (en) * | 2015-12-25 | 2016-04-20 | 夏放军 | Instant pidotimod and preparation technology thereof |
| CN113004265A (en) * | 2019-12-19 | 2021-06-22 | 鲁南制药集团股份有限公司 | Pidotimod histidine salt crystal form and preparation method thereof |
| CN111214446A (en) * | 2020-03-07 | 2020-06-02 | 瑞阳制药有限公司 | Peruvir L-arginine salt freeze-dried preparation for injection |
| CN111214446B (en) * | 2020-03-07 | 2022-02-25 | 瑞阳制药股份有限公司 | Peruvir L-arginine salt freeze-dried preparation for injection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1680427B (en) | 2010-08-11 |
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Owner name: SHUANGDING PHARMACEUTICAL CO., LTD, SHENYANG Free format text: FORMER OWNER: YANG XIHONG Effective date: 20121018 |
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Free format text: CORRECT: ADDRESS; FROM: 350001 FUZHOU, FUJIAN PROVINCE TO: 110179 SHENYANG, LIAONING PROVINCE |
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Effective date of registration: 20121018 Address after: Hi Tech road Shenyang city Liaoning province 110179 Hunnan New District No. 15 Patentee after: Shuangding Pharmaceutical Co., Ltd, Shenyang Address before: Fuzhou City, Fujian province 350001 Hualin Road No. 330 Building No. second room 1505 Jinghua collar Patentee before: Yang Xihong |