CN105663028B - A kind of per rectum administration double-layer sustained release suppository containing dianhydrogalactitol - Google Patents
A kind of per rectum administration double-layer sustained release suppository containing dianhydrogalactitol Download PDFInfo
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- CN105663028B CN105663028B CN201610098215.0A CN201610098215A CN105663028B CN 105663028 B CN105663028 B CN 105663028B CN 201610098215 A CN201610098215 A CN 201610098215A CN 105663028 B CN105663028 B CN 105663028B
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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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
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
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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
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
Abstract
The present invention is one kind suppository of double-layer sustained release containing dianhydrogalactitol and preparation method thereof, and preparation front end is bare substrate, and rear end is drug containing high molecular slow-release part.The drug of sustained release, in, lower hemorrhoidal veins enter body circulation, avoid decomposing in liver first-pass effect and alimentary canal.Dianhydrogalactitol content of the present invention is preferably 40mg.Suppository stable processing technique prepared by the present invention, it is at low cost, there is preferable Clinical practice value and social benefit.Suppository per rectum administration provided by the invention, for treating chronic granulocytic leukemia.
Description
Technical field
The present invention relates to field of medicine invention, and in particular to a kind of medicine for treating chronic granulocytic leukemia treatment
A kind of compositions, and in particular to double-layer sustained release suppository of the per rectum administration containing dianhydrogalactitol.
Background technology
Chronic myelocytic leukemia (Chronic Myelogenous Leukemia, CML) is a kind of influence blood and bone
The malignant tumour of marrow, fall ill in whole world leukaemia year 400000 people of number of cases or so, accounts for the 6th of various Cancer Mortalities；It can
See that leukaemia is to seriously endanger one of the malignant tumour of human health.Its feature is to generate a large amount of jejune leucocytes, these
Leucocyte is assembled in marrow, inhibits the normal hematopoiesis of marrow；And it can be spread in whole body by blood, patient caused to occur
Anaemia, easy bleeding, infection and organ infiltration etc.；The crowd at any age can be betided, but most with 50 years old or more crowd
Common, average age of onset is 65 years old, and male is more more conventional than women.
Chronic myelocytic leukemia is made slow progress, according toMarrowThe quantity of middle leukaemia cell and the severity of symptom,
It is divided into three phases：Chronic phase, accelerated period and rapid change period.Wherein, it is chronic phase when about 90% diagnosing patient, every year about 3%
Rapid change period is progressed to 4% chronic phase.Chronic phase the median survival time 3-5, once be changed into acute leukemia, then it is dead in a short time
It dies.At present in addition to Allogeneic Hematopoietic Stem Cell Transplantation, radical cure method is there is no, but can alleviate by drug therapy, it is main at present
Treatment means be by drug therapy extension patient chronic phase, improve its quality of life, prevent the deterioration of the state of an illness.
Up to the present, Allogeneic Bone Marrow Transplantation is to cure the most promising therapies of CML so far, but its success rate is only
It is 33% or so, and expense is up to hundreds thousand of, patient usually powerlessly bears.Therefore, clinically main treatment means, be still through
After radiotherapy or chemotherapy, conditions of patients is set to be alleviated by drug therapy.
Injection dianhydrogalactitol is hexasaccharide anticancer drug.The mechanism of action of dianhydrogalactitol has：
1, alkanisation：There is in vitro study report, DAG with the GGCC sequences on DNA by being combined, induced DNA fragmentation, from
And generate antitumor action.
2, promote apoptosis：Diacetyl dianhydrogalactitol (DADAG) can be lured by activating caspase (caspase)
Lead HL-60 Apoptosis.Caspase promotes apoptosis by the substrates such as PARP, lamin B, DFF45 of degrading.
3, Inhibit proliferaton：DADAG significantly can inhibit DNA of tumor cell to synthesize, and be in concentration dependent.This shows to inhibit
The intracellular DNA synthesis of Ehrlich tumor is one of the mechanism of DADAG killing tumor cells.
According to previous clinical data data, dianhydrogalactitol can inhibit the large biological molecules such as nucleic acid and albumen to synthesize, right
The transplanted tumor of animal has broad-spectrum anti-tumor activity, has the anticancer for the non-specific cell cycle for inhibiting cel l proliferation
Drug has a preferable short term effect to chronic myelocytic leukemia, remission rate 86%, and effective very fast, and drug combination can generate
Synergistic effect.There is apparent inhibition to various tumours and by blood-brain barrier, harmless to hepatic and renal function, no vascular stimulation is
What some other common anticancer drug cannot compare.
But injection dianhydrogalactitol category intravenous injection, the limitation in dosage form so that patient is difficult to adhere to long-term
Remissive treatment；In addition, when injection, if liquid exosmoses, local tissue necrosis may be caused, form ulcer.Therefore it should prevent when use
Only liquid exosmoses.
According to current market situation, it is repeatable to need to research and develop a kind of process stabilizing, at low cost, convenient drug administration, Bing Renyi
From the stronger drug-delivery preparation of property.
Dianhydrogalactitol is highly soluble in water, molecular weight very little, and molecular formula is with molecular weight：C6H10O4=146.14, structure
Formula is：
Two three-membered rings in dianhydrogalactitol molecule are unstable, meet the easy open loop of soda acid, lose therapeutic effect.According to its object
Rationality matter can be prepared into injection and mucosa delivery preparation.
Invention content
The object of the present invention is to provide a kind of double-layer sustained release suppository containing dianhydrogalactitol, front end is bare substrate, after
End is drug containing high molecular slow-release part.
It is a further object to provide a kind of preparation methods of dianhydrogalactitol double-layer sustained release suppository.
The present invention is realized by following technical solution：
The double-layer sustained release suppository of per rectum administration of the present invention containing dianhydrogalactitol, the suppository is by fore-end and rear end
Part forms, and the fore-end is bare substrate, and the rear end part is pastille slow-release matrix, which is characterized in that
The composition proportion of the bare substrate includes 10-17.5 parts of PLURONICS F87, poloxamer188 12.5-20
Part；
The composition proportion of the pastille slow-release matrix includes 1-4 parts of dianhydrogalactitol, 35-64 parts of PLURONICS F87, pool
Luo Shamu 407 40-70 part, 1.5-9 parts of Acritamer 940,7-18 parts of azone.
Preferably, the ingredient of bare substrate described in the double-layer sustained release suppository of per rectum administration of the present invention containing dianhydrogalactitol
Proportioning includes 13 parts of PLURONICS F87,17 parts of poloxamer188；
The composition proportion of the pastille slow-release matrix includes 4 parts of dianhydrogalactitol, 45 parts of PLURONICS F87, poloxamer
407 60 parts, 1.8 parts of Acritamer 940,9 parts of azone.
The suppository of dianhydrogalactitol of the present invention, it is characterised in that be prepared by following methods：
(1) auxiliary material needed for bare substrate formula is weighed, is heated to melting completely in water-bath, is injected in mold, it is cold
But spare after；
(2) PLURONICS F87, poloxamer188, Acritamer 940 are weighed to be heated to melting completely in water-bath, nitrogen is added dropwise
Sustained-release matrix is made in ketone, mixing；
(3) dianhydrogalactitol is taken, is sieved, is added in sustained-release matrix and stirs and evenly mixs；
(4) cold by the mold containing bare substrate in the pastille slow-release matrix liquid injection step (1) in step (3)
But after, redundance on mould is scraped off, is demoulded up to double-layer sustained release suppository.
Since existing dianhydrogalactitol is injecting drug use, there are medications inconvenient, liquid exosmoses the problems such as forming ulcer,
Accordingly, it is desirable to provide a kind of product for being convenient for carrying and using, increases medicine-feeding way, meets the market requirement.
Inventor devises double-layer sustained release suppository, and when use is placed in anus, and suppository front end is bare substrate, prevents patient
Administering position is excessively deep when use, and absorbs the drug from upper hemorrhoidal veins, into liver.Suppository rear end is containing dianhydrogalactitol
Slow-released part, drug can be directly entered blood circulation, avoid liver first-pass effect and break in, lower hemorrhoidal veins, anal canal vein
It is bad.Sustained-release administration is avoided to rectal mucosal irritation simultaneously.Dianhydrogalactitol is absorbed in a manner of non-oral, not by gastrointestinal tract pH
Or the destruction of enzyme, stimulation will not be generated to the stomach lining of patient, influence the normal diet of patient.
Traditional matrices suppository rectally often has sense of discomfort, because the matrix dissolved lacks stickiness, easily flowing cause leakage or
Move on to distal colon.Therefore the bare substrate of this double suppository and slow-released part use essentially identical temperature sensitive type in-situ gel
Agent, two parts, which combine, to be consolidated, and the gel of some strength can be formed under rectum physiological condition, be will not flow out or is moved after administration
Move on to distal colon.Temperature sensitive type in-situ gel agent simultaneously has hydrophily, and the dianhydrogalactitol of excellent aqueous solubility can be made slowly to release
It puts.Poloxamer is the common matrix of temperature sensitive type in-situ gel agent, is shared more typically with PLURONICS F87 and poloxamer188.
It is preferably 0.5-1.4 by PLURONICS F87 and poloxamer188 amount ratio after test of many times.Add in poloxamer matrix
Add carbomer that can reduce gelation temperature, improves gel strength and Bioadhesive force.Azone is mucosal absorption penetrating agent.
Using present invention process, have the following advantages that：
1, the present invention contains 1,2,5,6- two to the water wei ling alcohol of active constituent, for treating chronic granulocytic leukemia,
There is preferable short term effect.
2, the invention avoids dianhydrogalactitols is destroyed by liver first-pass effect and gastrointestinal tract pH or enzyme.
3, the present invention is particularly suitable for autonomous medication and long-term administration compared with injection.It is easy to carry, it is long-term for needing
The patient of medication substantially increases the compliance of patient, ensures therapeutic effect.
4, it can see from the comparison of comparative example and embodiment, the present invention is matched using preferred temperature sensitive type in-situ gel agent
Side avoids the too fast disadvantage of the drug release of traditional conventional substrate, has slow release effect.
5, preparation method process stabilizing of the present invention, repeatability is high, has novelty, is suitble to industrialized production.
Specific implementation mode
With reference to embodiment, the present invention is further illustrated.Content that the examples are merely illustrative, is never meaned
It to limit the scope of the invention in any way.
Main ingredient is 1,2,5,6- two to the water wei ling alcohol, and table 1 is 100 Formulations.
1 each experimental example prescription of dianhydrogalactitol double-layer sustained release suppository of table
Comparative example 1：
1, PEG4000 20g are taken, are heated to melting completely in 50 DEG C of water-baths, PEG400 10g are added dropwise, are noted with syringe
Enter in mold, it is spare after cooling per hole about 0.3g.
2, it presses prescription and measures PEG400076g, Acritamer 940 1.8g, be heated to melting completely in 60 DEG C of water-baths, be added dropwise
Sustained-release matrix is made in PEG400 38g and azone 9g, mixing.
3, dianhydrogalactitol 4.0g is taken by recipe quantity, sieved with 100 mesh sieve.Dianhydrogalactitol fine powder is added simultaneously into sustained-release matrix
It stirs and evenly mixs.
4, by the mold in the pastille slow-release matrix liquid injection step 1 of step (3), after cooling, it is extra on mould to scrape off
Part demoulds up to double-layer sustained release suppository.
Comparative example 2：
1, PLURONICS F87 15g, poloxamer188 15g are taken, is heated to melting completely in 60 DEG C of water-baths, with injection
Device injects in mold, spare after cooling per hole about 0.3g.
2, it presses prescription and measures PLURONICS F87 48g, poloxamer188 48g, HPMC K4M 10g, carbomer
940 1.8g are heated to melting completely in 60 DEG C of water-baths, and azone 9g is added dropwise, and sustained-release matrix is made in mixing.
3, dianhydrogalactitol 4.0g is taken by recipe quantity, sieved with 100 mesh sieve.Dianhydrogalactitol fine powder is added simultaneously into sustained-release matrix
It stirs and evenly mixs.
4, by the mold in the pastille slow-release matrix liquid injection step 1 of step (3), after cooling, it is extra on mould to scrape off
Part demoulds up to double-layer sustained release suppository.
Embodiment 1：
1, PLURONICS F87 10g, poloxamer188 20g are heated to melting completely, use syringe in 60 DEG C of water-baths
It injects in mold, it is spare after cooling per hole about 0.3g.
2, it presses prescription and measures PLURONICS F87 35g, poloxamer188 70g, Acritamer 940 1.8g, in 60 DEG C of water-baths
On be heated to melting completely, azone 9g is added dropwise, sustained-release matrix is made in mixing.
3, dianhydrogalactitol 4.0g is taken by recipe quantity, sieved with 100 mesh sieve.Dianhydrogalactitol fine powder is added simultaneously into sustained-release matrix
It stirs and evenly mixs.
4, by the mold in the pastille slow-release matrix liquid injection step 1 of step (3), after cooling, it is extra on mould to scrape off
Part demoulds up to double-layer sustained release suppository.
Embodiment 2：
1, PLURONICS F87 13g, poloxamer188 17g are taken, is heated to melting completely in 60 DEG C of water-baths, with injection
Device injects in mold, spare after cooling per hole about 0.3g.
2, it presses prescription and measures PLURONICS F87 45g, poloxamer188 60g, Acritamer 940 1.8g, in 60 DEG C of water-baths
On be heated to melting completely, azone 9g is added dropwise, sustained-release matrix is made in mixing.
3, dianhydrogalactitol 4.0g is taken by recipe quantity, sieved with 100 mesh sieve.Dianhydrogalactitol fine powder is added simultaneously into sustained-release matrix
It stirs and evenly mixs.
4, by the mold in the pastille slow-release matrix liquid injection step 1 of step (3), after cooling, it is extra on mould to scrape off
Part demoulds up to double-layer sustained release suppository.
Embodiment 3：
1, PLURONICS F87 17.5g, poloxamer188 12.5g are taken, is heated to melting completely in 60 DEG C of water-baths, is used
Syringe injects in mold, spare after cooling per hole about 0.3g.
2, it presses prescription and measures PLURONICS F87 64g, poloxamer188 40g, Acritamer 940 1.8g, in 60 DEG C of water-baths
On be heated to after melting completely, azone 9g is added dropwise, sustained-release matrix is made in mixing.
3, dianhydrogalactitol 4.0g is taken by recipe quantity, sieved with 100 mesh sieve.Dianhydrogalactitol fine powder is added simultaneously into sustained-release matrix
It stirs and evenly mixs.
4, by the mold in the pastille slow-release matrix liquid injection step 1 of step (3), after cooling, it is extra on mould to scrape off
Part demoulds up to double-layer sustained release suppository.
Embodiment 4：
1, PLURONICS F87 13g, poloxamer188 17g are taken, is heated to melting completely in 60 DEG C of water-baths, with injection
Device injects in mold, spare after cooling per hole about 0.3g.
2, it presses prescription and measures PLURONICS F87 45g, poloxamer188 60g, Acritamer 940 9g, in 60 DEG C of water-baths
It is heated to after melting completely, azone 7g is added dropwise, sustained-release matrix is made in mixing.
3, dianhydrogalactitol 4.0g is taken by recipe quantity, sieved with 100 mesh sieve.Dianhydrogalactitol fine powder is added simultaneously into sustained-release matrix
It stirs and evenly mixs.
4, by the mold in the pastille slow-release matrix liquid injection step 1 of step (3), after cooling, it is extra on mould to scrape off
Part demoulds up to double-layer sustained release suppository.
Embodiment 5：
1, PLURONICS F87 13g, poloxamer188 17g are taken, is heated to melting completely in 60 DEG C of water-baths, with injection
Device injects in mold, spare after cooling per hole about 0.3g.
2, it presses prescription and measures PLURONICS F87 45g, poloxamer188 60g, Acritamer 940 1.5g, in 60 DEG C of water-baths
On be heated to after melting completely, azone 18g is added dropwise, sustained-release matrix is made in mixing.
3, dianhydrogalactitol 4.0g is taken by recipe quantity, sieved with 100 mesh sieve.Dianhydrogalactitol fine powder is added simultaneously into sustained-release matrix
It stirs and evenly mixs.
4, by the mold in the pastille slow-release matrix liquid injection step 1 of step (3), after cooling, it is extra on mould to scrape off
Part demoulds up to double-layer sustained release suppository.
Quality evaluation is tested：
1, melt change overtime check：Melt by the version of Chinese Pharmacopoeia 2015 (four) and become time limit item inspection, takes 3 pieces of difference of suppository
It is placed on lower layer's plectane of 3 metal frames, is packed into respective sleeve, hook is used in combination to fix.Above-mentioned apparatus is immersed to Sheng respectively
Have in the container that temperature is 37 ± 0.5 DEG C, the upper end is away from water surface 90mm.It is primary that the device is overturn every lOmin.Water-soluble base
3 pieces of suppository should all be dissolved in 60min.
Experimental result：By each 3 pieces of suppositorys obtained of method in embodiment 1-5 and comparative example 1,2, oneself is molten in 60min
It solves (the results are shown in Table 2).
2 dianhydrogalactitol double-layer sustained release suppository of table, which melts, becomes the time limit
2, the inspection of release rate
Reference substance solution：Take dianhydrogalactitol reference substance appropriate, it is accurately weighed, add methanol that the control of about 100 μ g/mL is made
Product solution.
HPLC conditions：Chromatographic column：Agilent DB-1 (30m × 0.53mm, 1.5 μm)；Initial temperature is 100 DEG C, is maintained
3min rises to 200 DEG C with 10 DEG C/min, maintains 5min；Injector temperature is 250 DEG C, and detector FID temperature is 250 DEG C；Carrier gas
For nitrogen, flow velocity 5ml/min；Split ratio：1:10；Sampling volume is 1 μ l.Number of theoretical plate is calculated not low by dianhydrogalactitol peak
Separating degree between 20000, dianhydrogalactitol and each impurity should all meet regulation.
Suppository release：With reference to Chinese Pharmacopoeia version (four) dissolution rate in 2015 and the first method of drug release determination (Rotating shaker)
It measures.It respectively takes by 3 pieces of suppository made from method in embodiment 1-7, is respectively placed in dissolution test system.Rotating speed is set as
50rpm, temperature are 37 DEG C ± 0.5 DEG C, and dissolution medium is the phosphate buffer of pH7.4.Respectively at 0.5,1,2,4,6,8,12h
5ml is sampled, 0.45 μm of filtering with microporous membrane measures dianhydrogalactitol release rate, as a result such as table 3 with HPLC-ELSD methods.
3 dianhydrogalactitol double-layer sustained release suppository release rate of table
Suppository vitro release data fit zero level equation, and have good correlation, achieve the effect that sustained release.
1 drug release of comparative example being wherein prepared with raw material PEG using the way of typical bilayer suppository is fast, and uses pool Lip river husky
2 drug release of comparative example of nurse and hydroxypropyl methylcellulose is apparent excessively slow.Embodiment 1-3 releases in 12h are more than 85%, are had
Long-acting and good release, and its deenergized period at 12 hours or so, meet the daily life system rule of people.Therefore it is preferred that pool Lip river is husky
Nurse 188：The proportioning of poloxamer188 is 0.5-1.4 parts.
2,4,5 release of embodiment is close, although illustrating that Acritamer 940 can improve gel strength, its dosage is less, right
Release influences unobvious；And azone dosage has little effect vitro release.
Above example is merely to illustrate, and the application for not limiting to the present invention is carried out within the scope of present inventive concept
Addition, exchange, replacement etc., should also belong to the scope of protection of the present invention.
Claims (3)
1. a kind of double-layer sustained release suppository of the per rectum administration containing dianhydrogalactitol, the suppository is by fore-end and rear end part
Composition, the fore-end are bare substrate, and the rear end part is pastille slow-release matrix, which is characterized in that
The composition proportion of the bare substrate includes 10-17.5 parts of PLURONICS F87,12.5-20 parts of poloxamer188；
The composition proportion of the pastille slow-release matrix includes 1-4 parts of dianhydrogalactitol, 35-64 parts of PLURONICS F87, Bo Luosha
407 40-70 parts of nurse, 1.5-9 parts of Acritamer 940,7-18 parts of azone.
2. the double-layer sustained release suppository of the per rectum administration containing dianhydrogalactitol as described in claim 1, which is characterized in that
The composition proportion of the bare substrate includes 13 parts of PLURONICS F87,17 parts of poloxamer188；
The composition proportion of the pastille slow-release matrix includes 4 parts of dianhydrogalactitol, 45 parts of PLURONICS F87, poloxamer188
60 parts, 1.8 parts of Acritamer 940,9 parts of azone.
3. such as the double-layer sustained release suppository of per rectum administration of the claim 1-2 any one of them containing dianhydrogalactitol, feature
It is, is prepared by following methods：
（1）Auxiliary material needed for bare substrate formula is weighed, is heated to melting completely in water-bath, is injected in mold, after cooling
It is spare；
（2）It weighs PLURONICS F87, poloxamer188, Acritamer 940 to be heated to melting completely in water-bath, azone is added dropwise,
Sustained-release matrix is made in mixing；
（3）Dianhydrogalactitol is taken, is sieved, is added in sustained-release matrix and stirs and evenly mixs；
（4）By step（3）In pastille slow-release matrix liquid injection step（1）In in the mold containing bare substrate, after cooling,
Redundance on mould is scraped off, is demoulded up to double-layer sustained release suppository.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104095804A (en) * | 2013-04-09 | 2014-10-15 | 中国医学科学院药物研究所 | In-situ gel film agent with biological adhesion and preparation method thereof |
| CN104797267A (en) * | 2012-06-26 | 2015-07-22 | 德玛医药 | Methods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or ahi1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, or analogs or derivatives thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104797267A (en) * | 2012-06-26 | 2015-07-22 | 德玛医药 | Methods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or ahi1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, or analogs or derivatives thereof |
| CN104095804A (en) * | 2013-04-09 | 2014-10-15 | 中国医学科学院药物研究所 | In-situ gel film agent with biological adhesion and preparation method thereof |
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