CN1088914A - Pleuromutilin complexes - Google Patents
Pleuromutilin complexes Download PDFInfo
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- CN1088914A CN1088914A CN 93100102 CN93100102A CN1088914A CN 1088914 A CN1088914 A CN 1088914A CN 93100102 CN93100102 CN 93100102 CN 93100102 A CN93100102 A CN 93100102A CN 1088914 A CN1088914 A CN 1088914A
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- cyclodextrin
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- complex compound
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Abstract
Introduced by with the pleuromutilin derivative of the formula I of free alkali, acid salt or quaternary amine type and some complex compounds that cyclodextrin forms with contain the pharmaceutical preparation of this complex compound.This complex compound can be used as medicine (as microbiotic) according to proof with the method preparation of the above-mentioned pleuromutilin of complexing and a kind of suitable cyclodextrin, especially uses as veterinary drug, as using with the fodder additives form.
Description
The present invention relates to pleuromutilin derivative.Specifically, the pharmaceutical preparation that the invention provides the complex compound of pleuromutilin derivative and cyclodextrin and contain this complex compound.
Pleuromutilin derivative is the microbiotic that a series of pathogenic micro-organisms is had good microbiological activity.The pleuromutilin derivative of formula I particularly:
Be 14-O-(1-((D)-2-amino-3-methylbutyryl base amino)-2-methyl-prop-2-base ethanethioyl) pleurin (mutilin); under free alkali form or under acid salt or season (amine) salt form, be highly effective for many Gram-positives and gram negative bacterium.Owing to there are these character, can use above-claimed cpd as the microbiotic for the treatment of the disease of bringing out because of these pathogenic agent, wherein most of as veterinary medicine, for example be used for the treatment of the disease treatment of poultry, pig, domestic animal, sheep and goat, particularly respiratory tract disease and dysentery.
The cyclic oligomer carbohydrate that cyclodextrin is made up of D-pyrans (type) glucose unit of α (1 → 4)-connection, for example concerning α-, β-and γ-Huan Hujing, form by 6,7 and 8 unit respectively, in the literature, for example J.Szejtli work＜cyclodextrin technology＞(Kluwer Academic press, 1988) and D.Duchene work＜cyclodextrin and industrial application＞(Sante ' version, 1987) thereof among, to done detailed introduction.In preparation of the present invention, can use any cyclodextrin, for example α-, β-and γ-Huan Hujing or derivatives thereof.Preferred use β-or γ-Huan Hujing or derivatives thereof, especially β-or γ-Huan Hujing.α-, β-and γ-Huan Hujing be nontoxic compound, the drug excipient that they can be used as oral preparations uses and does not have danger.In addition, also allow a beta-cyclodextrin to use in many countries as the human foodstuff additive.
The derivative of cyclodextrin for example is the ethers that contains lower alcohol, as methyl flamprop or hydroxypropyl cyclodextrin etc.
People know from document, and cyclodextrin and suitable guest molecule can form inclusion compound (clathrate complex), but are difficult to expect the resulting effect of complex compound with forming.The character of preparation can draw according to the present invention, wherein has clathrate complex equally; Because only can not obtain viewed those required performances from pure physical mixture.
Observed unexpectedly phenomenon is: when formula I compound formed complex compound with cyclodextrin under free alkali form or under the quaternary amine form, the package stability of the performance of resulting pharmaceutical preparation, particularly fodder mixtures significantly improved.
As can be known, formula I compound is a known substance from the U.S. Pat P4675330 embodiment 12 of for example Sandoz.
When treatment or prevention Animal diseases, antibiotic preferred modes is to offer medicine in drinking-water or feed.Though can making things convenient for, the formula I compound under the water-soluble hydrochloride salt form, but is difficult to, because this material is decomposed as quick as thought by ingredient institute in traditional full fodder mixtures by means of the feed administration effectively by the drinking-water administration.Yet, to use for reality, the stability of the standby feed-medicinal mixture condition that is absolutely necessary is because must store it some months at least after producing this mixture material.
Therefore, people need a kind of like this preparation, and it has the stability of appropriateness and can offer medicine to animal by per os in standby fodder mixtures.For feed, except said stability requirement, other basic service requirements is good absorptivity, and production cost is low, and production process is simple and disposed the acceptability etc. of animal.
Find now, comprise, satisfy these requirements to a great extent with the formula I compound of free alkali, acid salt or quaternary amine form and the preparation of the formed complex compound of cyclodextrin.
Therefore, the present invention relates to the pleuromutilin derivative of aforesaid formula I with free alkali, acid salt or quaternary amine form and the complex compound of cyclodextrin, below brief note is made " complex compound of the present invention ".
The invention still further relates to and contain aforesaid acid salt or the formula I pleuromutilin derivative of quaternary amine form and the complex compound of cyclodextrin that is suitable for free alkali, medicine, also contain carrier or the pharmaceutical preparation of thinner, below brief note work " preparation of the present invention " that at least a medicine is suitable for simultaneously.
Complex compound of the present invention can be with a kind of like this method preparation, comprising carrying out complexing with formula I compound and a kind of suitable cyclodextrin of free alkali, acid salt or quaternary amine form.
Method of the present invention is pressed traditional way and is implemented, and preferably contacts with a kind of suitable cyclodextrin being suitable for forming under the condition of complex compound.Various traditional method modifications all can adopt.The aqueous solution of said compound and cyclodextrin is become dry, can adopt freeze-drying, spray-drying process and/or method of evaporation for this reason.Said complex compound can also utilize water to make physical mixture become the method for fully kneading after wet and make, in addition also can be in the method preparation of this pair of development component physical mixture in the ball mill for example.In addition, can obtain said complex compound by solution or solvent mixture crystalline method.
The ratio of formula I compound and cyclodextrin can change on a large scale; Mol ratio between this binary for example can about 1: 0.25 to about 1: 2, preferably approximately 1: 0.75 to about 1: 1.25, especially about 1: 1.
According to proof, for example use
1H-NHR spectrometry (stating experiment 3 as follows) proves, forms a kind of chemical bond between formula I compound and cyclodextrin molecular, and this key comprises hydrogen combination or Van der Waals force at least.
Preparation of the present invention is pressed the traditional way manufacturing, for example comprises that with a kind of mixing is by the suitable carrier of the formula I pleuromutilin derivative of the acid salt that is suitable for free alkali, medicine of above-mentioned definition or quaternary amine form and complex compound that suitable cyclodextrin forms and at least a medicine or the method manufacturing of thinner.
Preparation of the present invention can be made the preferably salt hydrochlorate in order to the formula I compound of free alkali shape or water-soluble or water-insoluble salt form.
Formed clathrate complex obtains more detailed description in following experiment:
1. phase-dissolubility picture
According to this phase-dissolubility picture (referring to D.Duchene work " cyclodextrin and industrial application thereof ", Sante ' version, in 1987, " research of inclusion compound and manufacture method and application thereof " literary composition), obtained following two types inclusion compound:
Chemical compounds I (alkali shape)-beta-cyclodextrin: A
LType
Chemical compounds I (alkali shape)-γ-Huan Hujing: B
SType.
For formula I compound, with β-and the complexation constant of γ-Huan Hujing be respectively 1050 M
-1With 1400 M
-1
2. calorimetry
When the complex compound of the hydrochloride of measuring formula I compound with microcalorimetry and beta-cyclodextrin (referring to " thermochemistry journal ", 109, the 139-143 page or leaf, the people such as L.E.Briggner of publication in 1986, " with diamantane-1-carboxylate salt microcalorimetric titration beta-cyclodextrin " literary composition), the complexation constant that records is 1004M
-1
3.
1The H-NMR spectrometry
With the formula I compound of hydrochloride shape and beta-cyclodextrin at D
2Solution among the O obtains
1On the H-NMR spectrum, with the pure solution of formula I compound
1H-NMR spectrum is compared, and has occurred obvious variation on signal location, and these change because of due to the following functional group:
Proton number formula I compound beta-cyclodextrin and formula Iization
The complex compound of (hydrochloride) compound
(ppm) (embodiment 3, ppm)
16 d0.73 s broadbands 0.69
17 d0.97 s broadbands 0.96
18 s1.45 s 1.49
8e d1.99 d 1.72
4 s2.56 s broadbands 2.58
20.20 dd5.24 dd broadband 5.35
19 dd, 6.37 s broadband～6.5
4. dsc
The preparation that the formula I compound by γ-Huan Hujing and hydrochloride shape of a kind of embodiment of being equivalent to 1 is formed, the bent heat of its differential scanning calorimetric has an endothermic signal (10 ° of K/min) at 193 ℃.
5. complex compound analysis
Be equivalent to Determination on content result in the preparation of embodiment 1: formula I compound (hydrochloride) 28.6%, H
2O 5.9%.The mol ratio that this content is equivalent to formula I compound (hydrochloride) and cyclodextrin is 1: 1.
In following non-restrictive example, temperature all refers to a degree centigrade value.
Embodiment 1
Heating is dissolved in 5.76 gram γ-Huan Hujings in the 18ml water down, adds 2.5 gram formula I compounds (hydrochloride).Stir down solution is cooled to 5 ℃.The white crystalline precipitate that comes down in torrents and form, dry in vacuum drying chamber.
Embodiment 2
Heating is dissolved in 7.8 gram beta-cyclodextrins in the 60ml water down, adds 3.87 gram formula I compounds (hydrochloride).With the solution decompression evaporate to dryness, dry residue is pulverized the back and is crossed the 1mm sieve.
Embodiment 3
Operate by the mode similar to embodiment 2, but solution spraying drying under 180 ℃ of air themperature.
Embodiment 4
Operate by the mode similar to embodiment 2, but solution be frozen to-40 ℃ of lyophilizes in 3 hours it.
Embodiment 5
Heating is dissolved in 2.9 gram γ-Huan Hujings in the 10ml water down, adds 2.5 gram formula I compounds (hydrochloride).Solution is spraying drying under 180 ℃ of air themperature.
Embodiment 6
Mix 7.7 gram formula I compounds (hydrochloride) and 15.5 gram beta-cyclodextrins, in kneading machine, add 15ml water.This wet material was fully kneaded 3 hours, then at vacuum drying chamber drying, crushing screening.
Embodiment 7
Mix 3.5 gram formula I compounds (hydrochloride) and 14.1 and restrain beta-cyclodextrins, grinding in ball grinder 6 hours.
Embodiment 8
Premixture
To be equivalent to the preparation of embodiment 1-7 and mash feed mixture and be mixed into 2% premixture, with the mash feed mixture that adds this premixture being diluted to formula I compound concentration in ball mill is 200ppm.
Embodiment 9
Granular fodder
Utilize suitable nodulizer and water vapor that the fodder mixtures of embodiment 8 is pressed into granular fodder.
The required character of some users of explanation preparation of the present invention in the following test:
1. feed stability
As typical feed, use standby forage feed piggy with following composition:
Oat 10.0%
Corn 29.0%
Barley 26.7%
Wheat 8.0%
Soybean chaff 23.0%
Lime carbonate 1.05%
Hydrogen-carbonate dicalcium 1.5%
Iodinating domestic animal salt 0.25%
Premixture (mineral substance-VITAMIN) 0.5%
Various forms of preparations are mixed with the standby feed that contains 200ppm formula I compound, store several weeks down for 30 ℃; Analyze the first content of fresh mixture and store 2,4 and 8 weeks content value afterwards with high pressure liquid chromatography (HPLC).
Table 1 explanation when using complex compound of the present invention in fodder mixtures, is compared with the corresponding preparations that does not contain cyclodextrin, and package stability improves.
Table 1
Fodder mixtures content (%)
Contain initial value 2 all backs after 48 weeks of back week
The compound 100 15 86 of formula I only
(hydrochloride)
The complex compound 100 89 87 90 of embodiment 3
The complex compound 100 91 92 88 of embodiment 6
In order to determine the optimum proportion between formula I compound and cyclodextrin, studied the cyclodextrin of various concentration.About the test-results of fodder mixtures package stability is compiled in the ratio that " ratio " in table 2(first row refers to formula I compound (hydrochloride) and beta-cyclodextrin).
Table 2
Content (%)
The ratio initial value is after January after February after March
1:0 100 9 9 7
1:2 100 86 89 91
1:1 100 90 89 96
1:0.75 100 49 45 38
1:0.5 100 18 9 8
1:0.25 100 14 8 9
2. mouthful absorption
Tested the absorbing state behind the preparation of giving mouse and pig dispensing 25mg/kg body weight embodiment 3, and with drinking-water in contain pure formula I compound (hydrochloride) contrast contrast.Blood sampling after 24 hours has been measured active material concentration in the blood plasma with microbiological analysis.The presentation of results of table 3 is with the sorption of complex form administration up-to-date style I compound of the present invention.
Table 3
Cmax (μ g/ml) AUC (during μ g/ml.)
Mouse pig mouse pig
Formula I compound 8.6 1.2 139 21.4 only
(hydrochloride)
The complex compound 11.7 1.6 294 24.3 of embodiment 3
Annotate: C
Max=maximal plasma concentration
The AUC=area under a curve.
Therefore proof: the complex compound of above-mentioned formula I pleuromutilin derivative with free alkali, acid salt that medicine is suitable for or quaternary amine form, as drug use, especially make as microbiotic and be used for treating the disease that Gram-positive and Gram-negative bacteria bring out, for example respiratory tract disease and dysentery.
For this purposes, used dosage can become with the sick body of used concrete complex compound, dosing mode, treatment and required treatment certainly.But, the day dispensing dosage of said complex compound is when being about 1mg/kg to about 100mg/kg body weight for the dosage of pig for example, during usually from about 5mg/kg to about 10mg/kg body weight, when every day was with agent administration in 2～4 fens in case of necessity, the general result who obtains satisfaction.
Complex compound of the present invention can be by the mode administration similar to the known substance that is used for these illnesss; The carrier and the thinner that can be suitable for traditional medicine, and with other selectivity mixed with excipients, and can be with form oral administrations such as granular fodder and premixtures.
Claims (9)
1, a kind of pleuromutilin derivative of the formula I with free alkali, acid salt or quaternary amine type:
Complex compound with cyclodextrin.
2, a kind of pharmaceutical preparation, wherein contain by claim 1 definition with the pleuromutilin derivative of the formula I of free alkali, acid salt that medicine is suitable for or quaternary amine type and complex compound and suitable carrier or the thinner of at least a medicine that cyclodextrin forms.
3, according to the complex compound of claim 1 or the pharmaceutical preparation of claim 2, wherein said formula I pleuromutilin derivative is the hydrochloride type.
4, according to the complex compound of claim 1 or the pharmaceutical preparation of claim 2, wherein said cyclodextrin is β-or γ-Huan Hujing.
5, according to the complex compound of claim 1 or the pharmaceutical preparation of claim 2, the mol ratio of wherein said pleuromutilin derivative and cyclodextrin is 1: 0.25～1: 2.
6, according to the complex compound of claim 1 or the pharmaceutical preparation of claim 2, wherein the mol ratio of pleuromutilin derivative and cyclodextrin is 1: 0.75～1: 1.25.
7, according to the complex compound of claim 1 or the pharmaceutical preparation of claim 2, wherein the mol ratio of pleuromutilin derivative and cyclodextrin is 1: 1.
8, a kind of method for preparing the complex compound of claim 1 is carried out complexing comprising formula I compound and a kind of suitable cyclodextrin with free alkali, acid salt or the quaternary amine type that make claim 1 definition.
9, a kind of method of making the pharmaceutical preparation of claim 2, comprising make claim 1 definition with free alkali, acid salt or the formula I pleuromutilin derivative of quaternary amine type and the complex compound that a kind of suitable cyclodextrin forms that medicine is suitable for, the carrier or the mixing diluents that are suitable for at least a medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93100102A CN1039585C (en) | 1993-01-01 | 1993-01-01 | Pleuromutilin complexes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93100102A CN1039585C (en) | 1993-01-01 | 1993-01-01 | Pleuromutilin complexes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1088914A true CN1088914A (en) | 1994-07-06 |
| CN1039585C CN1039585C (en) | 1998-08-26 |
Family
ID=4982800
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93100102A Expired - Fee Related CN1039585C (en) | 1993-01-01 | 1993-01-01 | Pleuromutilin complexes |
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| Country | Link |
|---|---|
| CN (1) | CN1039585C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1121216C (en) * | 1996-07-04 | 2003-09-17 | 生物化学有限公司 | Veterinary use of a pleuromutilin derivative |
| CN102344397A (en) * | 2011-08-23 | 2012-02-08 | 浙江升华拜克生物股份有限公司 | Method for purifying valnemulin hydrochloride |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8613688D0 (en) * | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| JPH0819004B2 (en) * | 1986-12-26 | 1996-02-28 | 日清製粉株式会社 | Sustained-release pharmaceutical preparation |
-
1993
- 1993-01-01 CN CN93100102A patent/CN1039585C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1121216C (en) * | 1996-07-04 | 2003-09-17 | 生物化学有限公司 | Veterinary use of a pleuromutilin derivative |
| CN102344397A (en) * | 2011-08-23 | 2012-02-08 | 浙江升华拜克生物股份有限公司 | Method for purifying valnemulin hydrochloride |
| CN102344397B (en) * | 2011-08-23 | 2013-09-04 | 浙江升华拜克生物股份有限公司 | Method for purifying valnemulin hydrochloride |
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| Publication number | Publication date |
|---|---|
| CN1039585C (en) | 1998-08-26 |
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