CN107669684A - A kind of matrix type sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet and preparation method thereof - Google Patents
A kind of matrix type sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet and preparation method thereof Download PDFInfo
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- CN107669684A CN107669684A CN201710977246.8A CN201710977246A CN107669684A CN 107669684 A CN107669684 A CN 107669684A CN 201710977246 A CN201710977246 A CN 201710977246A CN 107669684 A CN107669684 A CN 107669684A
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- sulfamethoxazole
- sulfadiazine
- trimethoprim
- sustained release
- release pellet
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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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
- A61K47/02—Inorganic compounds
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of oral medicinal sustained release preparation and preparation method thereof, more particularly to a kind of matrix type sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet and preparation method thereof, belong to pharmaceutical technology field.It is sustained capsule core by matrix type sulfamethoxazole, sulfadiazine and trimethoprim and film clothing forms, and wherein sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet is by sulphadiazine, Sulfamethoxazole, TMP, diluent, adhesive, sodium carbonate, framework material, coating material, anti-stick agent material are made by fluidized bed process.The sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet can be reached by sustained release to be reduced administration number of times, reduce administration accumulated dose and improves the purpose of cure rate, optimizes the clinical effectiveness of sulfamethoxazole, sulfadiazine and trimethoprim.
Description
Technical field
The present invention relates to slow control delayed release formulation of a kind of oral medicinal and preparation method thereof, more particularly to a kind of matrix type connection sulphur
TMP sustained release pellet and preparation method thereof, belong to pharmaceutical technology field.
Background technology
Sulfamethoxazole, sulfadiazine and trimethoprim is the compound preparation of sulphadiazine (SD), Sulfamethoxazole (SMZ) and TMP (TMP).
Sulphadiazine (SD) is white or crystallization or the powder of off-white color；It is odorless, it is tasteless, it is dark to meet photochromic gradual change.SD is in second
Slightly soluble in alcohol or acetone, it is almost insoluble in water；It is readily soluble in sodium hydroxide test solution or ammonia solution, dissolved in watery hydrochloric acid.SD
Oral easily to absorb, 3~4h reaches peak plasma concentrations, and protein binding rate is about up to the 70% of blood concentration, in blood for concentration in cerebrospinal fluid
45%, half-life period is 8~13h, and 30%~40% is discharged with original shape, 15%~30% with acetylated form from urinating after 24h.SD
Easily absorbed after oral from intestines and stomach, more than the 70% of about absorbable dosage, but absorb slower, 3~6 hours blood medicines after administration
Concentration peaking, the blood peak concentration of drug that dissociates after single oral 2g is about 30~60mg/L.Medicine solubility in urine is low, easily occurs
Crystalluria.
Sulfamethoxazole (SMZ) is white crystalline powder；It is odorless.SMZ is almost insoluble in water；Watery hydrochloric acid,
It is readily soluble in sodium hydroxide test solution or ammonia solution.Antimicrobial spectrum is similar to SD, but antibacterial action is stronger.The metabolism production of sulfa drug in vivo
The solubility of thing acetylate is low, easily separates out crystallization in urethra and causes crystalluria, blood urine and close urine etc., when heavy dose is applied
Preferably with sodium acid carbonate with clothes.Shared with synergist TMP, its antibacterial efficacy is remarkably reinforced, and can increase several times to tens times.It is clinical
For tonsillitis, acute bronchitis, pulmonary infection, urinary tract infections, skin pyogenic infection, bacillary dysentery and typhoid fever etc..
TMP (TMP) is white or off-white color crystalline powder；It is odorless.TMP is slightly molten in chloroform, in ethanol
Or slightly soluble in acetone, it is almost insoluble in water；It is readily soluble in glacial acetic acid.Antibacterial range and sulfa drug are close.Combine with sulfa drug
In use, several times to tens times of its curative effect can be strengthened.Suitable for respiratory tract infection, chronic senile bronchitis, bacillary dysentery, uropoiesis
The diseases such as system infections, enteritis, typhoid fever, malaria.As feed addictive, have substantially with sulfa drugs and antibiont and used time
Synergistic effect, can increase by ten to decades of times effect.It is not used alone, typically by 1：5 ratio uses, and can treat poultry large intestine
Septicemia, white diarrhea, avian typhoid, cholera, respiratory system Secondary bacterial infections etc. caused by bacillus.It can be additionally used in global-worm illness
Preventing and treating.
Sulfamethoxazole, sulfadiazine and trimethoprim category disulfonamide, there is good antibacterial to live to most of gram positive bacterias and negative bacterium
Property.It is in addition, also effective to coccidia, toxoplasm etc..SMZ and SD can compete dihydrofolate synthetase, resistance with p-aminobenzoic acid
Hinder dihydrofoilic acid and produce bacteriostasis, both have summation action at joint；TMP is then by suppressing the dihydrofolate reduction of bacterium
Enzyme, dihydrofolate reduction is hindered into tetrahydrofolic acid.Three shares plays double blocking to bacterium tetrahydrobiopterin synthesis folic acid process, its
Antibacterial action is remarkably reinforced.It should be noted that fully drinking water during medication, to reduce the crystallization infringement kidney in urine.
Sulfa drugs feature：Sulfa drugs solubility in urine is relatively low, and crystallization infringement kidney is formed easily in urine
It is dirty, preferably fully drunk water during medication, while take sodium acid carbonate alkalized urine and crystallized with reducing in urine.Dosage is excessive, then can
Increase toxic side effect, and dosage is too small, does not have therapeutic action not only, and pathogenic bacteria can be made to produce drug resistance on the contrary.It is, in general, that
Taking sulfa drug initial dose must double, and after treating acute stage, should also adhere to that medication can be discontinued for 3-4 days.Sulphadiazine, sulfanilamide (SN)
First oxazole 10-24h of drug half-life, belongs to middle effect class.
Sulfamethoxazole, sulfadiazine and trimethoprim is mainly administered in clinical practice in a manner of pre-mixing agent spice, and 3-5 days need to be used in conjunction, due to
There is medicine and inequality mixed with feed in spice, cause dosage insufficient or excessive, not have normal therapeutic effect, and often
Secondary feeding is required for dosing to mix, and administration is cumbersome.At the same time, need fully to give after administration to drink water, take appropriate sodium carbonate,
To reduce the crystallization infringement kidney in urine.
In order to preferably be applied to clinical practice, now develop it is a kind of facilitate clinical administration, while reduce administration number of times, be administered
The sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet to animal body damage is reduced afterwards.
The content of the invention
Technical problem solved by the invention is to overcome existing sulfamethoxazole, sulfadiazine and trimethoprim pre-mixing agent dosage is not in the application
Easy control, sulfa drugs is to the renal toxicity of animal body, sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet side after cumbersome and administration is administered
Just spice or direct administration, administration number of times taper to daily 1-2 times, and animal body interior energy remains certain in a long time after being administered
Effective blood drug concentration, avoid peak valley occur before being administered again, advantageously reduce the toxic side effect of medicine, reduce and total agent is administered
Amount, reaches maximum drug effect with minimum dosage.In addition, the present invention further provides sulfamethoxazole, sulfadiazine and trimethoprim of the present invention sustained release is micro-
Ball, its method is simple, and auxiliary material is selectively wide, suitable for industrialized production.
The present invention is achieved through the following technical solutions：
The present invention directly can be completed pill operation by fluid bed in actual production, be realized by fluid bed pill method
A tractor serves several purposes, without additionally individually purchasing device for producing a granulated material.
The present invention uses matrix type sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet.
The invention provides a kind of matrix type sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet, and it mainly has following raw material by described weight
Number is measured to form：
The diluent of the present invention is sucrose, one or more combinations in lactose, glucose.
The present invention adhesive for polyethylene glycol 400, hydroxypropyl cellulose, carboxymethyl cellulose, HPMC,
One or more combinations in polyacrylic resin.
Sodium acid carbonate in the present invention can effectively alleviate the toxic side effect of sulfa drugs.
The framework material of the present invention is ethyl cellulose, polymethacrylates, cellulose acetate, non-toxic polyvinyl chloride etc.
One or more combinations in water-insoluble framework material.
The coating material of the present invention is polyacrylic resin.
The antiplastering aid of the present invention is talcum powder, one or more combinations in PEG, stearic acid.
Present invention also offers a kind of preparation method of matrix type sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet, comprise the following steps：
The raw material of following number is weighed respectively：
(2) 1. by sulfanilamide (SN) pyrimidine, Sulfamethoxazole, TMP, sodium acid carbonate, sucrose, the broken mesh of mistake 80 of ethyl cellulose
Sieve, which puts the 20min that seethed with excitement in fluid bed, to be made uniformly；2. taking PVOH 400 to add, appropriate stirring solvent is uniform, and adjustment spraying frequency is opened
Begin to spray；3. adding antiplastering aid according to pelletization situation in fluid bed prevents viscous ball phenomenon；4. after in fluid bed without fine powder
The ethanol solution of polyacrylic resin is taken to open spray coating；It is boiled below that 5. computer heating control temperature 60 C is opened after the completion of coating
Dry.
There is sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet provided by the present invention spice to use easily mixing, the convenient administration of Direct-fed
The advantages of, reach the purpose of sustained release after administration by sustained-release matrix, it is excellent so as to maintain animal body effective blood drug concentration for a long time
Change the clinical therapeutic efficacy of sulfamethoxazole, sulfadiazine and trimethoprim.
Brief description of the drawings
Fig. 1 is sulfanilamide (SN) pyrimidine, Sulfamethoxazole, the blood concentration of TMP total concentration, wherein series 1 is control, series 2 is
1 group is formulated, is that class 3 is 1 group of formula, series four is 3 groups of formula.
Embodiment
The supplementary material proportioning of the sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet of the present invention of embodiment 1.
Screening formula presses the raw material proportioning of following parts by weight, formula 1- formulas 3.
The raw material of formulation weight number in above-mentioned table is weighed respectively, takes sulfanilamide (SN) pyrimidine, Sulfamethoxazole, TMP, sugarcane
Sugar, polyethylene glycol 400, put and cross 80 mesh sieves in pulverizer after crushing, putting the 20min that seethed with excitement in fluid bed is well mixed raw material, separately
Taking adhesive opens shower nozzle after being diluted with water.
Take formula 4 and the sulfamethoxazole, sulfadiazine and trimethoprim pre-mixing agent (100g commonly used in clinic：Sulphadiazine 20g+ Sulfamethoxazoles
20g+ TMP 8g) pharmacodynamics test is done, pass through the mutation analysis present invention connection sulphur of drug in blood serum concentration in certain time
Whether TMP micropill, which can reach expected, maintains more stable blood concentration purpose.
Beneficial effects of the present invention are proved below by way of specific pharmacodynamics test.
The medicine pharmacokinetics experiment of the present invention of test example 1
A reagents and animal
50-55kg health pig is randomly divided into four groups, respectively control group, 1 group of formula, 2 groups of formula, 3 groups of formula, often
Group 8, adapts to environment one week after packet, it is former to award sulphadiazine raw material 40mg, Sulfamethoxazole for disposable gavage after fasting 12h
The sulfamethoxazole, sulfadiazine and trimethoprim micropill of isodose is formulated 1 group, formula 2 groups and formula after material 40mg, TMP raw material 16mg, and conversion
3 groups.After gavage respectively at 0h, 0.25h, 0.5h, 0.75h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 20h, 24h,
30h, 36h gather peripheric venous blood in anticoagulant tube, and separated plasma saves backup.
B sample treatments
The blood plasma 500ul being collected is taken, 5ml acetonitriles is added, is well mixed with liquid-transfering gun, puts 6000r/ in supercentrifuge
Min centrifugations 15 are quick, after 0.22um filtering with microporous membrane, take subsequent filtrate 20ul sample introductions to analyze.
C detection methods
Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica, with acetonitrile-water-three
Ethamine (200:799:1) it is mobile phase (to adjust pH value to 5.9 with sodium hydroxide test solution or glacial acetic acid)；Detection wavelength is 240nm.
Number of theoretical plate is calculated by TMP peak is not less than 4000, the separating degree of Sulfamethoxazole, sulphadiazine peak and TMP peak
Regulation should be met.
Separately take Sulfamethoxazole reference substance, sulphadiazine reference substance and TMP reference substance appropriate, it is accurately weighed, add
0.1mol/l hydrochloric acid solutions dissolve and quantify dilution be made in every 1ml containing about Sulfamethoxazole 0.2mg, sulphadiazine 0.2mg with
TMP 80ug solution, shakes up, and is measured in the same method, and by external standard method with calculated by peak area, produces.
Test apparatus：Shimadzu LC-20 high performance liquid chromatographs detect.
D test datas count, and every group measures sulfanilamide (SN) pyrimidine, Sulfamethoxazole, TMP total concentration and blood medicine can be used as dense
Angle value, six data measured remove a maximum, remove a minimum value, take the average value of remaining six data to count
Analysis, statistical result are as shown in table 1：
M- blood concentration standard curve when being drawn according to Fig. 1, and result is analyzed.
Fig. 1, standard curve：
Can intuitively it be found by standard curve, after sulfamethoxazole, sulfadiazine and trimethoprim is pelleting, highest blood concentration compares control group
It is low, and peak time evening, but it is pelleting after the fall off rate of blood concentration be obviously reduced, can maintain in a long time compared with
High blood concentration, and the micropill of different sustained release rates can be made by adjusting each component proportion in micropill, optimization connection
The clinical application effect of sulphur TMP.
2 medicine effect of the present invention of test example is tested
A clinical application protocols：Luoyang sick pig is taken, random packet.
Blank control group：Sick pig 5, normal feeding, is not administered, continuous 7 days.
Test 1 group：Sick pig 20, normal feeding, the sulfamethoxazole, sulfadiazine and trimethoprim pre-mixing agent (100g produced with our company：Sulfanilamide (SN)
Pyrimidine 20g+ Sulfamethoxazole 20g+ TMP 8g) press per 1000kg feeds, the feeding of pig 100g spices, early, middle and late each one
It is secondary, it is used in conjunction 5, continues observation 2 days after drug withdrawal.
Test 2 groups：Sick pig 20, normal feeding, pressed with 3 made sulfamethoxazole, sulfadiazine and trimethoprim micropills of formula and raised per 1000kg
Material, the feeding of pig 100g spices, early, evening, respectively once noon was not administered once, is used in conjunction 5, continued observation 2 days after drug withdrawal.
Observation daily once, records Cure, as a percentage.As a result statistics is as shown in table 2：
As shown in Table 2, the sulfamethoxazole, sulfadiazine and trimethoprim micropill and sulfamethoxazole, sulfadiazine and trimethoprim pre-mixing agent of same amount specification, micropill energy
Enough in the case where reducing administration number of times and administration quantity, reach the treatment with the normal dosage of sulfamethoxazole, sulfadiazine and trimethoprim pre-mixing agent
Effect, effect is better than general formulation in the identical treatment cycle, and cure rate is higher than general formulation.
Claims (9)
1. a kind of matrix type sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet, it is characterised in that it mainly presses the parts by weight by following raw materials
It is prepared：Sulphadiazine, Sulfamethoxazole, TMP, diluent, adhesive, sodium carbonate, framework material, coating material,
Anti-stick agent material.
2. sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet according to claim 1, it is characterised in that it is mainly pressed by following raw materials
The parts by weight are prepared：
3. sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet according to claim 1, it is characterised in that described diluent is sucrose, breast
One or more combinations in sugar, glucose.
4. sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet according to claim 1, it is characterised in that described adhesive is poly- second two
One or more groups in alcohol 400, hydroxypropyl cellulose, carboxymethyl cellulose, HPMC, polyacrylic resin
Close.
5. sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet according to claim 1, it is characterised in that described framework material is ethyl
One or more in the water-insoluble framework material such as cellulose, polymethacrylates, cellulose acetate, non-toxic polyvinyl chloride
Combination.
6. sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet according to claim 1, it is characterised in that described coating material is poly- third
Olefin(e) acid resin.
7. sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet according to claim 1, it is characterised in that described antiplastering aid be talcum powder,
One or more combinations in PEG, stearic acid.
8. sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet according to claim 1, it is characterised in that urinated to alleviate sulfa drugs
Middle crystallization infringement kidney adds the sodium carbonate of doses.
A kind of 9. method of the sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet prepared described in claim 1, it is characterised in that including following step
Suddenly：It will be well mixed, utilize after the diluent for meeting the parts by weight, water-insoluble framework material, sodium acid carbonate, crushing
Matrix type sustained release pellet is made in fluidized bed process spray adhesive, and film clothing suspension finally is sparged into micropill surface, adds antiplastering aid,
It is dried to obtain sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710977246.8A CN107669684A (en) | 2017-10-19 | 2017-10-19 | A kind of matrix type sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710977246.8A CN107669684A (en) | 2017-10-19 | 2017-10-19 | A kind of matrix type sulfamethoxazole, sulfadiazine and trimethoprim sustained release pellet and preparation method thereof |
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| Publication Number | Publication Date |
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| CN107669684A true CN107669684A (en) | 2018-02-09 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050260263A1 (en) * | 2004-05-18 | 2005-11-24 | Panion & Bf Biotech Inc. | Sustained release formulation for sparingly soluble main drugs |
| CN101987091A (en) * | 2009-08-07 | 2011-03-23 | 北京天衡药物研究院 | Venlafaxine hydrochloride sustained-release pellet capsules |
| CN103536604A (en) * | 2013-10-31 | 2014-01-29 | 成都乾坤动物药业有限公司 | Wettable sulfamethoxazole trimethoprim powder and preparation method thereof |
| CN105903019A (en) * | 2016-05-17 | 2016-08-31 | 湖南泰谷生物兽药有限公司 | Compound sulfanilamide soluble powder and preparation method thereof |
-
2017
- 2017-10-19 CN CN201710977246.8A patent/CN107669684A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050260263A1 (en) * | 2004-05-18 | 2005-11-24 | Panion & Bf Biotech Inc. | Sustained release formulation for sparingly soluble main drugs |
| CN101987091A (en) * | 2009-08-07 | 2011-03-23 | 北京天衡药物研究院 | Venlafaxine hydrochloride sustained-release pellet capsules |
| CN103536604A (en) * | 2013-10-31 | 2014-01-29 | 成都乾坤动物药业有限公司 | Wettable sulfamethoxazole trimethoprim powder and preparation method thereof |
| CN105903019A (en) * | 2016-05-17 | 2016-08-31 | 湖南泰谷生物兽药有限公司 | Compound sulfanilamide soluble powder and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 贾林军、许建国: "《动物药理学》", 31 January 2017, 中国轻工业出版社 * |
| 陈兴荣等: "缓控释微丸的研究进展", 《中国兽药杂志》 * |
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Application publication date: 20180209 |