CN101269216A - Oral preparation for reducing brinolase, preparation method and uses thereof - Google Patents
Oral preparation for reducing brinolase, preparation method and uses thereof Download PDFInfo
- Publication number
- CN101269216A CN101269216A CNA2007100383583A CN200710038358A CN101269216A CN 101269216 A CN101269216 A CN 101269216A CN A2007100383583 A CNA2007100383583 A CN A2007100383583A CN 200710038358 A CN200710038358 A CN 200710038358A CN 101269216 A CN101269216 A CN 101269216A
- Authority
- CN
- China
- Prior art keywords
- defibrase
- preparation
- enteric coated
- micropill
- enteric
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention discloses a novel fiber reducing enzyme oral preparation, which contains enteric dissolved preparation the main component of which is fiber reducing enzyme. The invention also provides the preparation method and the purpose of the fiber reducing enzyme oral preparation. The preparation can be clinically used for treating or preventing diseases such as: (1) acute cerebral infarction, including cerebral thrombosis, cerebral embolism, transient cerebral ischemia attack, and cerebral infarction recrudescence; (2) myocardial infarction, unstable angina, and myocardial infarction recrudescence; (3) vascular disease in limbs, including femoral artery embolism, thromboangitis obliterans, and Raynauds disease; (4) blood in high-viscosity state, hypercoagulability state, and pro-thrombotic state; (5) sudden deafness; (6) pulmonary embolism; etc.
Description
Technical field
The present invention relates to a kind of Defibrase oral formulations, and the method for making of described Defibrase oral formulations and purposes.
Background technology
Defibrase is the single component batroxobin (Thrombin like) that extracts purification from snake venom, has the similar effect of blood plasma thrombin, and the function of falling fibre, thromboembolism preventing, thrombolytic is arranged.Batroxobin (ThrombinLikeenzyme) is the product that certain curative effect arranged of the international generic drugs of The World Health Organization (WHO) with the name name, and it has arginine esterase and thrombin activity.Because the difference of Serpentis kind, there are many products to come out, such as the Ancrod that records through WHO evaluation and name and British Pharmacopoeia, reptilase Reptilas (the Venoms of Agkistrodon acutus in the plain tall and big pharmaceutical factory of Basel, SUI, haemocoagulase haemocoagulase) and the batroxobin (Batroxobin that produces of Japan, separate in the snake venom by the subspecies Bothropsmoojeni of Brazilian fer-de-lanc, the refining acquisition, be mainly serine protease SerineProtease etc.), wherein batroxobin is made preparation " Batroxobin " through Japanese Johoson Mattey Pharmaceutic Industries K.K..
The Chinese Defibrase ministry standard of formulating by international medicine quality standard of the same race according to ministry of Health of China in 1997 [(97) defend the medicine marking-up No. 01), homemade Defibrase is to be to separate one-component batroxobin (the Thrombin Like Enzyme that purifies from Changbai Mountain agkistrodon halys ussuriensis or Agkistrodon acutus venom, TLE), belong to proteolytic enzyme, molecular weight is about 36000, and the Defibrase activity is no less than 1200 units (U) (representing with U/mg under the specific activity unit) in the specific activity 1mg albumen.The reduction plasma fibrinogen is arranged, suppressing thrombosis generates, bring out the blood vessel endothelium tissue and discharge t-PA, thrombus, also have blood viscosity lowering and blood fat, inhibiting erythrocyte aggregation and platelet aggregation strengthen erythrocyte deformability, therefore effects such as microcirculation improvement have powerful anticoagulant, thrombolytic effect.
The Defibrase preparation that uses clinically at present is freeze-dried powder (5U/ props up, 10U/ prop up), and said preparation can be used for acute cerebral infarction, comprises cerebral thrombosis, cerebral embolism, transient ischemic attack, and the cerebral infarction prevention of recurring again; Myocardial infarction, the prevention that unstable angina pectoris and myocardial infarction recur again; Limb angiopathy comprises the femoral artery thromboembolism, thromboangiitis obliterans, Raynaud disease; Blood is high viscosity and high coagulant state, hypercoagulability, the preceding state of thrombosis; Sudden deafness; Pulmonary infarction etc. have the medication number of times few, short treating period, the characteristics of few side effects.
But there is shortcoming in the Defibrase ejection preparation, at first, and to the condition height of injection production requirement, producing cost height; Secondly, bring pain to patient during injection; Moreover, use inconvenience, said preparation need face with before, make it dissolving with an amount of water for injection or normal saline, therefore requirement comes strictness to carry out sterile working and injection by the people who is skilled in technique.Because Defibrase itself is a protease, adopt the common oral preparation administration will cause Defibrase major part in stomach to be degraded, Defibrase also is difficult to be absorbed at the intestines and stomach, and bioavailability is very low, therefore is difficult to reach the purpose of oral administration treatment.
In sum, this area presses for the non-ejection preparation of developing a kind of convenient drug administration and highly active Defibrase can being provided.
Summary of the invention
Purpose of the present invention just provides a kind of convenient drug administration and the oral enteric preparation of highly active Defibrase can be provided.
Another object of the present invention provides the method for making and the purposes of the oral enteric preparation of described Defibrase.
In a first aspect of the present invention, a kind of Defibrase oral formulations is provided, described oral formulations is enteric coated preparation and has following characteristic:
(i) containing the Defibrase protein content in every dose is 0.0001-20mg;
(ii) measure by the following method, behind oral this preparation, the highest blood drug level of Defibrase reaches 0.2-3U/L blood: be the described preparation of SD rat oral administration of 250 ± 10g to body weight, continuous three days, once a day, dosage is corresponding to the 0.01mg Defibrase, and measures the blood drug level of Defibrase after administration in the 3rd day; With
(iii) the specific activity of described Defibrase is 400-8000U, preferably is 500-4000U/mg albumen, more preferably is 800-3000U/mg albumen.
In another preference, described preparation release rate of Defibrase in simulated gastric fluid is no more than 6%.
In another preference, described release rate is no more than 5%, more preferably is no more than 3%.
More preferably, described release rate is measured with the enzyme activity method of demarcating, and calculates with following formula:
In another preference, the release rate of described preparation Defibrase in simulated intestinal fluid is greater than 90%.In another preference, described release rate is greater than 95%, more preferably greater than 96%.The computing formula of release rate is as follows:
In another preference, described preparation is disintegrate in 40 minutes in simulated intestinal fluid.
More preferably, described preparation disintegration time in simulated intestinal fluid is in 30 minutes.
In another preference, described preparation is selected from down group:
(a) enteric coated tablet, described tablet comprises medicated core and enteric coatings, wherein said medicated core contains Defibrase and pharmaceutically acceptable carrier;
(b) enteric coated capsule, described capsule comprise enteric coated capsule and are positioned at the drug powder or the granule of enteric coated capsule that wherein said drug powder or granule contain Defibrase and pharmaceutically acceptable carrier; Or
(c) enteric coated micropill agent, the enteric coated micropill that described pellet comprises capsule and is positioned at capsule, wherein said enteric coated micropill comprises micropill medicated core and enteric coatings, wherein said micropill medicated core contains Defibrase and pharmaceutically acceptable carrier.
In another preference, described enteric coatings can be first preparation Defibrase granule, carries out film-making again after directly adopting the enteric solubility material to be wrapped in the granule outside then, also can be with enteric material bag sheet after the Defibrase granule film-making for preparing.
In another preference, described pharmaceutically acceptable carrier comprises: filler, binding agent, disintegrating agent or swellability adjuvant, wetting agent, fluidizer, antitack agent, aromatic, sweeting agent.
Preferably, described disintegrating agent is selected from down group: starch, modified starch, hydroxypropyl starch, carboxymethyl starch sodium, microcrystalline Cellulose, cellulose derivative (comprising methylcellulose, carboxy-propyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, low replacement-hyprolose, cross-linking sodium carboxymethyl cellulose carboxymethylcellulose calcium), crospolyvinylpyrrolidone, tween 80, sodium lauryl sulphate, guar gum, Herba Xanthii glue, xanthan gum or its combination.
In another preference, described preparation is the enteric coated preparation that discharges at small intestinal, large intestine (comprising colon) or rectum.
In another preference, every dose of protein content that contains Defibrase is 0.001-10mg, more preferably 0.01-10mg in the described preparation.
In another preference, described Defibrase comprises Serpentis Defibrase (as the Defibrase of Agkistrodon halys).
In another preference, it is the Defibrase raw material that every mg albumen contains the active 600-4000U of Defibrase that oral formulations adopts specific activity.
In a second aspect of the present invention, the present invention is provided the purposes of above-mentioned Defibrase oral formulations, and described preparation is used to prepare treatment or prevents the medicine of following disease: (1) acute cerebral infarction comprises cerebral thrombosis, cerebral embolism, transient ischemic attack, and the cerebral infarction prevention of recurring again; (2) myocardial infarction, unstable angina pectoris and myocardial infarction recur again; (3) limb angiopathy comprises the femoral artery thromboembolism, thromboangiitis obliterans, Raynaud disease; (4) blood is high viscosity and high coagulant state, hypercoagulability, the preceding state of thrombosis; (5) sudden deafness; (6) pulmonary infarction.
In a third aspect of the present invention, the preparation method of the oral formulations of the above-mentioned Defibrase of the present invention is provided, the method comprising the steps of:
In tablet medicated core outer wrap enteric coatings, thereby form enteric coated tablet, wherein said medicated core contains Defibrase and pharmaceutically acceptable carrier; Perhaps
With drug powder or particle packing in enteric coated capsule, thereby form enteric coated capsule, wherein said drug powder or granule contain Defibrase and pharmaceutically acceptable carrier; Perhaps
Enteric coated micropill is filled in the capsule, thereby form the enteric coated micropill agent, wherein said enteric coated micropill comprises micropill medicated core and enteric coatings, and wherein said micropill medicated core contains Defibrase and pharmaceutically acceptable carrier; Perhaps
Enteric coated micropill and pharmaceutically acceptable carrier mixing back tabletting are prepared into enteric coatel tablets, and wherein said enteric coated micropill comprises micropill medicated core and enteric coatings, and wherein said micropill medicated core contains Defibrase.
The specific embodiment
The problem that the inventor exists in view of existing Defibrase ejection preparation, the extensive studies through going deep on the basis of screening a large amount of prescriptions and preparation technology, is made Defibrase the oral enteric preparation first.Experiment showed, that Defibrase oral enteric preparation of the present invention has good effectiveness, safety and good patient compliance and toleration.Finished the present invention on this basis.
Term
Medicated core among the present invention is meant that (piller is removed the part of enteric coatings in Pellets), contains Defibrase and pharmaceutically acceptable carrier in the medicated core at enteric coated tablet or enteric coated micropill.
As used herein, term " simulated intestinal fluid " finger print is intended the liquid of mammal intestinal juice.Simulated intestinal fluid can be prepared according to Chinese Pharmacopoeia, also can use phosphate buffer (pH6.8).A kind of preferred manufacturing procedure is as follows: get potassium dihydrogen phosphate 6.8g, add water 500ml and make dissolving, regulate pH value to 6.8 with the 0.1mol/L sodium hydroxide solution, get pancreatin 10g, add water and make dissolving, after two liquid were mixed, thin up promptly got simulated intestinal fluid to 1000ml.(seeing 158 pages of 2005 editions second appendix of Chinese Pharmacopoeia).
As used herein, term " simulated gastric fluid " finger print is intended the liquid of mammal gastric juice.Simulated gastric fluid can be prepared according to Chinese Pharmacopoeia, also can use the 0.1mol/L hydrochloric acid solution.A kind of preferred manufacturing procedure is as follows: get dilute hydrochloric acid 16.4ml, add about 800ml of water and pepsin 10g, after shaking up, add the water weighing apparatus and release to 1000ml, promptly get simulated gastric fluid (seeing 72 pages of 2005 editions second appendix of Chinese Pharmacopoeia).
Active component
In the present invention, active component is a Defibrase.Being applicable to that Defibrase of the present invention is not particularly limited, can be the Defibrase of various routines, comprising (but being not limited to): the Defibrase that extracts from all kinds of Serpentiss (as Agkistrodon halys).Preferred Defibrase is the Defibrase that derives from Changbai Mountain agkistrodon halys ussuriensis or Agkistrodon acutus.These Defibrases can extract or preparation with conventional method.
Be that the natural Defibrase or the Defibrase of recombination engineering mode production all can be used for the present invention.
Usually its specific activity of Defibrase raw material that uses as ejection preparation 1200U/mg or more than, in the present invention, since Defibrase as oral formulations in factor affecting such as formulation preparation loss, gastrointestinal absorption, degraded inactivations, target protein absorbs factors such as overall control, the drug level window (bound of blood drug level) that reaches optimum therapeuticing effect, cost of material after considering the single oral administration, usually the specific activity that is used as the active component Defibrase raw material of oral formulations should and be lower than 8000U/mg greater than 200U/mg, more preferably, be 600-4000U/mg.
Certainly, in preparation of the present invention, also can contain other active substances or the auxiliary element that helps to fall fine effect.
Enteric coated preparation and method for making thereof
Enteric coated preparation of the present invention mainly comprises:
(a) enteric coated tablet, described tablet comprises medicated core and enteric coatings, wherein said medicated core contains Defibrase and pharmaceutically acceptable carrier; Wherein, described enteric coatings can be first preparation Defibrase granule, carries out film-making again after directly adopting the enteric solubility material to be wrapped in the granule outside then, also can be with enteric material bag sheet after the Defibrase granule film-making for preparing.
(b) enteric coated capsule, described capsule comprise enteric coated capsule and are positioned at the drug powder or the granule of enteric coated capsule that wherein said drug powder or granule contain Defibrase and pharmaceutically acceptable carrier;
(c) enteric coated micropill agent, the enteric coated micropill that described pellet comprises capsule and is positioned at capsule, wherein said enteric coated micropill comprises micropill medicated core and enteric coatings, wherein said micropill medicated core contains Defibrase and pharmaceutically acceptable carrier.
Usually, in oral enteric preparation of the present invention, every dose contains Defibrase 0.0001-20mg, filler 0-200mg, binding agent 0-200mg, disintegrating agent or swellability adjuvant 0-300mg, lubricant 0.1-20mg, fluidizer 0.1-15mg, antitack agent 0-15mg etc., and wherein active substance Defibrase (calculating with albumen weight) is 0.0001-20mg.
Described filler is selected from starch, dextrin, Icing Sugar, lactose, mannitol, calcium hydrogen phosphate or microcrystalline Cellulose, cellulose, also can be their mixture.
Described wetting agent is selected from water or ethanol, or their mixture.
Described binding agent is selected from a kind of of starch slurry, hydroxypropyl starch, modified starch, pregelatinized Starch, dextrin, Icing Sugar, syrup, microcrystalline Cellulose, cellulose derivative (comprising hydroxypropyl emthylcellulose, methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose), polyvinylpyrrolidone rubber cement, gelatine size, or their mixture.
Described disintegrating agent or swellability adjuvant are selected from hydroxypropyl starch, modified starch, starch, carboxymethyl starch sodium, microcrystalline Cellulose, cellulose derivative (comprises hydroxypropyl emthylcellulose, methylcellulose, sodium carboxymethyl cellulose, low replacement-hyprolose, cross-linking sodium carboxymethyl cellulose, carboxy-propyl cellulose, carboxymethylcellulose calcium), crospolyvinylpyrrolidone, tween 80, sodium lauryl sulphate, guar gum, Herba Xanthii glue, a kind of in the xanthan gum or their mixture.
Described lubricant, fluidizer, antitack agent can be selected a kind of in modified starch, microcrystalline Cellulose, aluminium hydroxide, boric acid, sodium benzoate, Polyethylene Glycol, stearic acid, magnesium stearate, calcium stearate, zinc stearate, Pulvis Talci, Stepanol MG, sodium lauryl sulphate or micropowder silica gel, glycerol monostearate, rice-pudding paulownia acyl tristerin, hydrogenant Oleum Ricini, hydrogenated vegetable oil, light mineral oil, the Fumaric acid octadecyl sodium or their mixture for use.
Can also increase aromatic and sweeting agent in prescription when doing tablet, can be a kind of in stevioside, essence or the aspartame or their mixture.
Coating material comprises enteric solubility acrylic resin, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, Lac etc.
Oral enteric preparation of the present invention can be made with the method and apparatus of this area routine.
In a preference, temperature (as 4-15 ℃) in the control production environment, humidity (is lower than 40%RH, be preferably lower than 20%RH) under the condition, while draws moist owing to raw material has, adjuvant moisture all in the preparation process will be controlled, under the situation about keeping dry, in every dose, contain Defibrase 5-800mg, filler 0-200mg, binding agent 0-200mg, disintegrating agent or swellability adjuvant 0-300mg, lubricant 0.1-20mg, fluidizer 0.1-15mg, antitack agent 0-15mg etc., with active substance Defibrase (being calculated as 5-500mg) and various types of pharmaceutical carriers or adjuvant uniform mixing, obtain mixture with albumen weight.
The preparation method of enteric coated tablet generally includes steps such as granulation, tabletting, coating.
The preparation method of enteric coated capsule generally includes granulation, step such as encapsulated.
The preparation method of enteric coated micropill generally includes: the preparation method of micropill has coating pan method, centrifugal lamination method, spherocrystal comminution granulation, emulsion process, extrudes spheronization, methods such as ebullated bed is granulating coated, oscillating drop method for making, and concrete operating procedure is variant.
In another preference, the gained mixture is prepared into microcapsule, carry out tabletting after coating be prepared into enteric coatel tablets, perhaps microcapsule is filled to and makes enteric coated capsule in the enteric capsule shell, perhaps microcapsule is made enteric coated micropill.
Also can adopt ball-type micropill comminutor to prepare micropill, wherein control process conditions: production environment and device temperature remain on below 10 degree.The micropill diameter is controlled in the 2mm.
Adopt different prescriptions, medicine can be made common, the rapid release or the micropill of disintegrate (controlled release) fast, be packed into jejunum colloidal sol capsule or adopt enteric coating to be pressed into tablet and use.
Defibrase albumen is not degraded in gastric juice and activity is not hindered mistake in order to reach, simultaneously can be in intestinal the rapid release absorbed purpose of coming out, by following two conditions control preparation process:
(1) preparation of enteric coated preparation mode, enteric coated preparation mode can be first with enteric material and the micropill that Defibrase albumen mixing index becomes to have the enteric characteristics, adopt such micropill to remove tabletting, encapsulating capsule more then, thereby accomplish enteric on the micropill level; Also can be first with behind the Defibrase protein Preparation micropill, repress sheet bag enteric material, or fill enteric coated capsule.
(2) disintegrate fast; after by the enteric mode Defibrase being delivered to intestinal portion; guarantee that Defibrase is distributed to the intestinal surface fast to be absorbed; adopt micropill and quickly disintegrated two mode combinations; the purpose that distributes fast again with the activity of protective enzyme; quickly disintegrated adjuvant prepares micropill after can mixing with Defibrase together, also can be after micropill prepares again and quick disintegrate adjuvant mixed pressuring plate.
The micropill of rapid release (fast release micropill) is the micropill with very fast drug release rate that Defibrase and general adjuvant are made, generally speaking, the 30min dissolution must not be less than 70%, normal a certain amount of disintegrating agent or the surfactant of adding in the micropill prescription is with the quick disintegrate of assurance micropill and the stripping of Defibrase.
Preferred mode, Defibrase earlier behind the parcel enteric material again and fast the disintegrate adjuvant mix, with the activity of protective enzyme, be not subjected to the influence of disintegrate adjuvant and inactivation.
The adjuvant of ball core mainly contains diluent and binding agent,
Ball core adjuvant commonly used has sucrose, lactose, starch, microcrystalline Cellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose etc.
The adjuvant of micropill coating membrane has the coating filmogen, and plasticizer need add porogen, coloring agent, antiplastering aid and lucifuge agent etc. sometimes.Water-soluble plasticizer commonly used has triethyl citrate, glycerol, propylene glycol, polyethylene glycols; Fat-soluble plasticizer has triethyl citrate, dimethyl phthalate, dibutyl sebacate, triacetin, Semen Ricini wet goods; Porogen commonly used has polyethylene glycols, polyvinylpyrrolidone, sucrose, salt and other water soluble film-forming materials such as HPMC, HPC etc.; Resistance to bond commonly used has Pulvis Talci, micropowder silica gel, magnesium stearate; Sometimes also must add coloring agent, stabilizing agent, surfactant such as sodium lauryl sulphate, defoamer such as dimethicone in the coating fluid prescription in addition.
The method that can be used for preparing micropill of the present invention is not particularly limited, and can use the existing method and apparatus in this area.1), rotation roller pill the preparation method of micropill can reduce four big classes substantially according to device type and preparation process:; 2), the laminated type pill, comprise liquid-layering method and powder type lamination method; 3), squash type pill; 4), spheroidization pill.
The preparation equipment of micropill and technology have traditional coating pan and fast type coating pan, fluid bed and centrifugal fluidization equipment centrifugal granulator, extruding-spheronizator and in liquid medium the intra-liquid desiccation method and the ball-type crystallization granulation technology of preparation micropill.The preparation method of micropill also can utilize microcapsule technology of preparing such as chemical polymerization to make the micropill of desirable particle size except the above four big class.
Though above-mentioned four kinds of modes all can reach the purpose of preparation micropill, but consider the protein properties of Chinese medicine of the present invention and enzymatic activity to be easy to receive physics (heat, pressure etc.) and chemistry (acid, alkali, denaturant, surfactant etc.) factor and cause the characteristics of inactivation that the condition that will take into full account various process procedures is in process of production controlled.
Preferably, the micropill preparation process condition should be considered low temperature (it is following that temperature is controlled at 15 degree Celsius), dry (production environment humidity is controlled at below 8%) and factor such as tabletting pressure is low, speed is low.
In preference,, can under the working condition of control, directly adopt microcapsule technology with proenzyme material package quilt, again with other various types of pharmaceutical carriers or adjuvant uniform mixing in order further to solve protease inactivation problem in process of production.
The capsule material and the carrier material that can adopt when being prepared into microcapsule comprise: gelatin, arabic gum, alginate, protide (comprising albumin, as human serum albumin, bSA, zein, egg albumen, calf casein etc.), starch (comprising corn starch, wheaten starch, potato starch etc.) and carboxymethyl cellulose, O-phthalic acid cellulose, methylcellulose, ethyl cellulose, hypromellose, cellulose acetate butyrate, succinic acid cellulose acetate etc.Poly-carbon ester, polyamino acid, polylactic acid, polyacrylic resin, polymethyl methacrylate, poly hydroxy ethyl acrylate, paracyanogen base alkyl acrylate, second are imitated ester lactide copolymer, polylactic acid-polyglycol block copolymer, ε-caprolactone and lactide block copolymer, polymeric anhydride and carboxymethyl glucose etc.
In a preference, enteric coated preparation of the present invention is the Defibrase enteric coated capsule, every dose comprises Defibrase 0.005-5mg, starch 0-200mg, microcrystalline Cellulose 0-200mg, crospolyvinylpyrrolidone 2-200mg, cross-linking sodium carboxymethyl cellulose 0-200mg, low replacement-hyprolose 0-200mg, micropowder silica gel 0-15mg, magnesium stearate 0.1-20mg, sodium lauryl sulphate 0-15mg.
Its preparation method comprises:
Take by weighing Defibrase, starch, microcrystalline Cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, low replacement-hyprolose, mix homogeneously;
Dropwise 5 % polyvinylpyrrolidone K30 ethanol liquid system soft material is crossed the 18-24 mesh sieve and is granulated;
Wet granular mild wind under low temperature dries up and carries out drying;
With 18-24 mesh sieve granulate, add magnesium stearate and micropowder silica gel mixing, be filled in the enteric coated capsule, promptly obtain the Defibrase enteric coated capsule.
In another preference, enteric coated preparation of the present invention is the Defibrase enteric coatel tablets, and every comprises Defibrase 0.005-5mg, starch 0-200mg, microcrystalline Cellulose 0-200mg, crospolyvinylpyrrolidone 2-200mg, cross-linking sodium carboxymethyl cellulose 0-200mg, low replacement-hyprolose 0-200mg, micropowder silica gel 0-15mg, magnesium stearate 0.1-20mg, sodium lauryl sulphate 0-15mg, stevioside 0-15mg.
Its preparation method comprises:
Take by weighing Defibrase, starch, microcrystalline Cellulose, partial cross-linked polyvinylpyrrolidone, partial cross-linked sodium carboxymethyl cellulose, the low replacement-hyprolose of part, mix homogeneously;
Dropwise 5 % polyvinylpyrrolidone K30 ethanol liquid system soft material is crossed the 18-24 mesh sieve and is granulated;
Wet granular is the mild wind drying under low temperature;
Adopt the enteric solubility material, comprise coatings such as enteric solubility acrylic resin, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, Lac;
With 18-24 mesh sieve granulate, add remaining crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, low replacement-hyprolose, magnesium stearate and micropowder silica gel, mixing tabletting by aforementioned formula again.
Among all embodiment, if the Defibrase raw material ratio activity that adopts is higher, used protein content compares less, occurs problems such as the raw material dispersion is irregular, supplementary material incomplete mixing in actual mechanical process easily, therefore will guarantee raw material and the abundant mix homogeneously of adjuvant in the process of feeding intake.Such as, can be by earlier the Defibrase and the starch of significant proportion (being no more than 1: 5) fully being mixed, and then mix with various adjuvants again as raw material this mixture is pro rata, progressively the mode of amplification quantity guarantees the abundant mixing of supplementary material.
Administering mode
Oral enteric preparation of the present invention can pass through oral administration.Usually the absorbing state according to Defibrase raw material ratio activity, preparation changes the protein content of preparation, with dosage every day of under physician guidance, determining concrete patient, press active dosage every day that calculates single patient of Defibrase, certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are the work within the skilled practitioners skill.
Oral formulations of the present invention can be used for treating various diseases and the symptom that present Defibrase injection is suitable for, comprising (but being not limited to): be used for the treatment of or prevent (1) acute cerebral infarction, comprise cerebral thrombosis, cerebral embolism, transient ischemic attack, and cerebral infarction recurs again; (2) myocardial infarction, unstable angina pectoris and myocardial infarction recur again; (3) limb angiopathy comprises the femoral artery thromboembolism, thromboangiitis obliterans, Raynaud disease; (4) blood is high viscosity and high coagulant state, hypercoagulability, the preceding state of thrombosis; (5) sudden deafness; (6) disease such as pulmonary infarction.
The major advantage of Defibrase oral formulations of the present invention comprises:
(a) with respect to drug administration by injection, oral formulations is taken more convenient.
(b) Defibrase protein active height in preparation of the present invention has been guaranteed after the oral absorption effectively.
(c) do not degrade basically by preparation way Defibrase in gastric juice activity that is protected, and the preparation enteric solubility is good, the protease major part is absorbed at intestinal, the blood drug level height.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, The theory and practice of industrialpharmacy (Lachman L) or " pharmaceutics " third edition (chief editor such as Tu Xide for example, the People's Health Publisher publishes) and " novel pharmaceutical formulation and new technique " (Lu Bin chief editor, the People's Health Publisher, 1998) condition described in, or the condition of advising according to manufacturer.
The preparation of embodiment 1, Defibrase enteric coated capsule
Get Defibrase 0.2g (albumen weight, be 2000U/mg albumen than living) and carboxymethyl cellulose salt 15g, low-substituted hydroxypropyl cellulose 15g, fully mixing such as crospolyvinylpyrrolidone 10g, gelatin 5g, be prepared into microcapsule, then microcapsule and microcrystalline Cellulose 5g, starch 25g, Pulvis Talci are fully mixed, the enteric coated capsule of packing into No. 3, be prepared into 1000 enteric coated capsulees, each capsule contains the 0.2mg Defibrase.
Present embodiment makes multiple batches of capsule, and wherein getting lot number at random is 0901,0902, and 0903 detects.
The preparation of embodiment 2, Defibrase enteric coatel tablets
Getting Defibrase 0.2g (being about 1500U/mg albumen than living) and carboxymethyl cellulose salt 15g, low-substituted hydroxypropyl cellulose 10g, crospolyvinylpyrrolidone 4g, gelatin 5g etc. fully mixes, granulate, cold doing, the cellulose acetate phthalate coating, cross the 18-24 mesh sieve, then with microcrystalline Cellulose 5g, starch 25g, crospolyvinylpyrrolidone 4g, cross-linking sodium carboxymethyl cellulose 4g, low replacement-hyprolose 5g, an amount of magnesium stearate and micropowder silica gel, 1000 of mixing pressures.Every contains the 0.2mg Defibrase.
Present embodiment makes multiple batches of enteric coatel tablets, and wherein getting lot number at random is 1011,1012, and 1013 detect.
The antiacid performance of embodiment 3, enteric coated preparation
In the present embodiment, simulated gastric fluid is the 0.1mol/L hydrochloric acid solution.
The Defibrase enteric coated capsule and the enteric coatel tablets of preparation among the embodiment 1 are positioned in the 100mL simulated gastric fluid, mixing speed is no more than 200r/min in 37 ± 1 ℃ water bath with thermostatic control, in 2 hours, measure the content of Defibrase in the simulated gastric fluid, find to have to be no more than 6% Defibrase and to discharge.
Table one, enteric coated preparation capacity antacid
The result of table one shows: the preparation according to the formulation of embodiment 1 and 2 is stable in gastric environment.
The enteric performance of embodiment 4, enteric coated preparation
Get potassium dihydrogen phosphate 6.8g, add water 500ml and make dissolving, regulate pH value to 6.8 with the 0.1mol/L sodium hydroxide solution, get pancreatin 10g, amount of water makes dissolving, and after two liquid were mixed, thin up obtained simulated intestinal fluid to 1000ml.
Defibrase enteric coated capsule and enteric coatel tablets are positioned in the 100mL simulated intestinal fluid, and mixing speed is no more than 200r/min in 37 ± 1 ℃ water bath with thermostatic control, measures the content of Defibrase in the simulated intestinal fluid in 1 hour, finds to have the Defibrase above 96% to discharge.
The enteric performance of table two, enteric coated preparation
The result of table two shows: the preparation according to the formulation of embodiment 1 and 2 can go out Defibrase by rapid release in the intestinal environment.
The stability of embodiment 5, enteric coated preparation
Put into saturated nacl aqueous solution in the exsiccator bottom, 3 batches of Defibrase enteric coated capsulees and enteric coatel tablets sample are put in top, seal, and exsiccator is put in 40 ± 1 ℃ of constant incubators and placed 90 days continuously, every sampling in 30 days once, measure.
Table three, constant temperature and humidity accelerated test result (40 ± 1 ℃ of temperature, humidity 75%)
The result of table three shows: the enteric coated preparation according to the formulation of embodiment 1 and 2 is stable to temperature.
The oral absorption of embodiment 6, enteric coated preparation is measured
Defibrase adopts
125I (radioiodine) labelling according to the prescription of embodiment 1, adopts animal specific enteric coated capsule (the special-purpose enteric capsule shell of the toy that capsule for medicine factory in Shantou provides) to be prepared into enteric coated capsule, and every capsule contains 2mg Defibrase labelled protein.Adopt the Defibrase labelled protein to prepare conventional capsule in a conventional manner simultaneously and do contrast, each conventional capsule also contains 2mg Defibrase albumen.Adopt the SD rat, 7 every group, gastric infusion, before administration and after the administration 30,45,60 minutes respectively, eye socket was got blood, measures in the 100uL blood
125I content of radioactive substance (calculating) with radiocounting, result such as table four.
Behind table four, the gastric infusion in the SD rat blood
125The radioactive mensuration of I
The result of table four shows: in 60 minutes, with respect to ordinary preparation bigger absorption is arranged according to the enteric coated preparation of the formulation of embodiment 1.
The activity in vivo of embodiment 7, enteric coated preparation
Estimate the purpose that whether can effectively absorb behind the oral enteric Defibrase preparation for reaching, the activity of Defibrase in the body behind the needs mensuration oral administration, this part work divides following several contents:
1), adopt chloramine-t method to carry out isotope
125I (Na
125I) labelling Defibrase, Sephadex G50 separation and purification, mark rate is 40.1%, and specific activity is 25.03kBq/ug, and the radiochemicsl purity that adopts SDS-PAGE electrophoresis technique determining label is greater than 95%, and the Defibrase behind the labelling is measured its biological activity and is not obviously reduced.
2), adopt the 4mg labelling Defibrase (
125The I Defibrase) under laboratory condition, according to embodiment 1 preparation a small amount of micropill, canned toy contains the Defibrase of 0.01mg with in the enteric coated capsule in each capsule.It is qualified to measure its enteric characteristic according to embodiment 3 and embodiment 4.
3), the SD rat (6, male, 250 ± 10g) oral administrations, continuous three days, once a day, the Defibrase (1 capsule is directly sent in the stomach) of each 0.01mg, before the administration first time and administration in the 3rd day after 0,30,60,120 minutes, eye socket is got blood and is gone into to add in the Eppendorf pipe of heparin, get blood 0.5-0.8ml at every turn, centrifugal 5 minutes of 3000rpm, it is standby as sample to be determined to get supernatant blood plasma.
4), the standard curve of preparation trichloroacetic acid (TCA) sedimentation method and two kinds of mensuration of SDS-PAGE: at first prepare 0.01M, the phosphate buffer preparation of pH6
125(Concentraton gradient is 12.5,50,200,800 to I Defibrase standard solution, 3200ng/ml); In 0.5ml Eppendorf centrifuge tube, respectively add standard solution 10ul, normal mice blood plasma 15ul, distilled water 175ul and trichloroacetic acid 200ul according to the trichloroacetic acid precipitation method then, 12000rpm is centrifugal 3 minutes behind the mixing, abandon supernatant, centrifuge tube is placed directly in the radioactivity determination pipe, measure 60 second radioactivity γ counting, with this calculate radiocounting and
125The linear relationship of I Defibrase concentration.
The result shows: in the said determination scope, radiocounting and
125I Defibrase concentration has good linear relationship, and this method is measured in the blood plasma
125The signal to noise ratio of I Defibrase concentration is 3.1, and minimum detectable activity is 2.4ng/ml.
With top
125I Defibrase standard solution 10ul, add the cold 1mg/ml Defibrase of equal-volume, carry out the SDS-PAGE electrophoresis after the heating, after electrophoresis is finished, Coomassie brilliant blue R-250 dyeing, row decolouring again, every swimming is with equidistant crosscut to become adhesive tape, carry out radioactivity determination respectively, calculate Defibrase position adhesive tape in the swimming band the gross activity counting and
125The concentration of I Defibrase is linear.
The result shows: in the said determination scope, in the swimming band gross activity of Defibrase position adhesive tape counting and
125I Defibrase concentration has good linear relationship, and this method is measured in the blood plasma
125The signal to noise ratio of I Defibrase concentration is 2.8, and minimum detectable activity is 2.1ng/ml.
5), get the prepared sample to be determined of third step, carry out the TCA method respectively according to the 4th step respectively and the SDS-PAGE method is measured, contrast prepared standard curve, calculate the Defibrase concentration in the blood behind the oral Defibrase.
The result is as follows:
1) adopt present embodiment institute describing method, TCA method and SDS-PAGE method all can effectively detect
125Defibrase amount behind the I labelling, its radiocounting and Defibrase concentration are the good linear relation.
2) in the sample to be determined
125I Defibrase amount is in prepared standard curve range.
3) two kinds of methods contrast, unanimity as a result, dependency is fine.
4) result who measures by said method shows:
Oral Defibrase enteric coated preparation according to embodiment 1 preparation is after 30 minutes, have only minute quantity Defibrase amount to be detected in the blood, Defibrase content after oral 60 minutes in the blood is 0.2-3U/L (change being arranged according to individual variation), be up to 3U/L, blood still can detect the existence of Defibrase after 120 minutes.
In contrast, be contrast (dosage is identical with mode) with Defibrase conventional capsule (non-enteric coated preparation)., detect less than the Defibrase amount in the blood after 30 minutes, after 60 minutes and after 120 minutes at oral contrast capsule.
Hence one can see that, compares with Defibrase conventional capsule (non-enteric coated preparation) in contrast, and Defibrase enteric coated preparation of the present invention has better activity in vivo.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. a Defibrase oral formulations is characterized in that, described oral formulations is enteric coated preparation and has following characteristic:
(i) containing the Defibrase protein content in every dose is 0.0001-20mg;
(ii) measure by the following method, behind oral this preparation, the highest blood drug level of Defibrase reaches 0.2-3U/L blood: be the described preparation of SD rat oral administration of 250 ± 10g to body weight, continuous three days, once a day, dosage is corresponding to the 0.01mg Defibrase, and measures the blood drug level of Defibrase after administration in the 3rd day; With
(iii) the specific activity of described Defibrase is a 500-4000U/mg albumen.
2. oral formulations as claimed in claim 1 is characterized in that, described preparation release rate of Defibrase in simulated gastric fluid is no more than 6%.
3. oral formulations as claimed in claim 1 is characterized in that, the release rate of described preparation Defibrase in simulated intestinal fluid is greater than 90%.
4. Defibrase oral formulations as claimed in claim 1 is characterized in that described preparation is disintegrate in 40 minutes in simulated intestinal fluid.
5. Defibrase oral formulations as claimed in claim 1 is characterized in that, described preparation is selected from down group:
(a) enteric coated tablet, described tablet comprises medicated core and enteric coatings, wherein said medicated core contains Defibrase and pharmaceutically acceptable carrier;
(b) enteric coated capsule, described capsule comprise enteric coated capsule and are positioned at the drug powder or the granule of enteric coated capsule that wherein said drug powder or granule contain Defibrase and pharmaceutically acceptable carrier; Or
(c) enteric coated micropill agent, the enteric coated micropill that described pellet comprises capsule and is positioned at capsule, wherein said enteric coated micropill comprises micropill medicated core and enteric coatings, wherein said micropill medicated core contains Defibrase and pharmaceutically acceptable carrier.
6. Defibrase oral formulations as claimed in claim 5 is characterized in that, described pharmaceutically acceptable carrier comprises: filler, binding agent, disintegrating agent or swellability adjuvant, wetting agent, fluidizer, antitack agent, aromatic, sweeting agent.
7. Defibrase oral formulations as claimed in claim 6, it is characterized in that described disintegrating agent is selected from down group: starch, modified starch, hydroxypropyl starch, carboxymethyl starch sodium, microcrystalline Cellulose, cellulose derivative, crospolyvinylpyrrolidone, tween 80, sodium lauryl sulphate, guar gum, Herba Xanthii glue, xanthan gum or its combination.
8. Defibrase oral formulations as claimed in claim 1 is characterized in that, described preparation is the enteric coated preparation that discharges at small intestinal, large intestine (comprising colon) or rectum.
9. the purposes of Defibrase oral formulations as claimed in claim 1, it is characterized in that described preparation is used to prepare treatment or prevents the medicine of following disease: (1) acute cerebral infarction comprises cerebral thrombosis, cerebral embolism, transient ischemic attack, and the cerebral infarction prevention of recurring again; (2) myocardial infarction, unstable angina pectoris and myocardial infarction recur again; (3) limb angiopathy comprises the femoral artery thromboembolism, thromboangiitis obliterans, Raynaud disease; (4) blood is high viscosity and high coagulant state, hypercoagulability, the preceding state of thrombosis; (5) sudden deafness; (6) pulmonary infarction.
10. the preparation method of the oral formulations of the described Defibrase of claim 1 is characterized in that, comprises step:
In tablet medicated core outer wrap enteric coatings, thereby form enteric coated tablet, wherein said medicated core contains Defibrase and pharmaceutically acceptable carrier; Perhaps
With drug powder or particle packing in enteric coated capsule, thereby form enteric coated capsule, wherein said drug powder or granule contain Defibrase and pharmaceutically acceptable carrier; Perhaps
Enteric coated micropill is filled in the capsule, thereby form the enteric coated micropill agent, wherein said enteric coated micropill comprises micropill medicated core and enteric coatings, and wherein said micropill medicated core contains Defibrase and pharmaceutically acceptable carrier; Perhaps
Enteric coated micropill and pharmaceutically acceptable carrier mixing back tabletting are prepared into enteric coatel tablets, and wherein said enteric coated micropill comprises micropill medicated core and enteric coatings, and wherein said micropill medicated core contains Defibrase.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100383583A CN101269216A (en) | 2007-03-23 | 2007-03-23 | Oral preparation for reducing brinolase, preparation method and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100383583A CN101269216A (en) | 2007-03-23 | 2007-03-23 | Oral preparation for reducing brinolase, preparation method and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101269216A true CN101269216A (en) | 2008-09-24 |
Family
ID=40003608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100383583A Pending CN101269216A (en) | 2007-03-23 | 2007-03-23 | Oral preparation for reducing brinolase, preparation method and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101269216A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104083756A (en) * | 2014-07-22 | 2014-10-08 | 张庆宇 | Auxiliary agent for stabilizing pharmaceutical composition and pharmaceutical composition containing auxiliary agent |
| CN114712491A (en) * | 2021-12-15 | 2022-07-08 | 北京斯耐客科技发展有限责任公司 | Preparation method of gelatin enzyme activity protective agent and application of gelatin enzyme activity protective agent in defibrase preparation |
-
2007
- 2007-03-23 CN CNA2007100383583A patent/CN101269216A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104083756A (en) * | 2014-07-22 | 2014-10-08 | 张庆宇 | Auxiliary agent for stabilizing pharmaceutical composition and pharmaceutical composition containing auxiliary agent |
| CN104083756B (en) * | 2014-07-22 | 2015-12-02 | 张庆宇 | A kind of adjuvant of stabilizing pharmaceutical composition and the pharmaceutical composition containing this adjuvant |
| CN114712491A (en) * | 2021-12-15 | 2022-07-08 | 北京斯耐客科技发展有限责任公司 | Preparation method of gelatin enzyme activity protective agent and application of gelatin enzyme activity protective agent in defibrase preparation |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4976968A (en) | Anhydrous delivery systems for pharmacological agents | |
| CN101987081B (en) | Controlled release preparation | |
| KR100685303B1 (en) | Gastric-retentive, oral drug dosage forms for the controlled-release of sparingly soluble drugs and insoluble matter | |
| AU643753B2 (en) | Thrombin composition for oral administration | |
| TWI609693B (en) | Stable digestive enzyme compositions | |
| DK170244B1 (en) | Device for controlled release of active substances and method for preparing such device | |
| US5194464A (en) | Enteric film and preparatoin thereof | |
| Ciper et al. | Modified conventional hard gelatin capsules as fast disintegrating dosage form in the oral cavity | |
| CA2318257A1 (en) | Novel dosage form | |
| MXPA02001272A (en) | Hydrodynamically balancing oral drug delivery system. | |
| US20080031947A1 (en) | Orally dissolvable/disintegrable lyophilized dosage forms containing protected | |
| KR20040018333A (en) | Oral formulations containing mucopolysaccharide for small intestine delivery and their use in the treatment circulatory disorders | |
| US20110182987A1 (en) | Pharmaceutical dosage form for the site-specific delivery of more than one active pharmaceutical ingredient | |
| US4601895A (en) | Delayed-action acetylsalicylic acid formulations for oral administration | |
| ZA200402066B (en) | Expandable gastric retention device. | |
| KR101708086B1 (en) | Pharmaceutical or neutraceutical formulation | |
| CN101249081A (en) | Administer orally controlled release drug administration pharmaceutical tablet | |
| CN101269216A (en) | Oral preparation for reducing brinolase, preparation method and uses thereof | |
| Kumar et al. | A comprehensive review on sustained release Matrix drug Delivery system | |
| CN101658482A (en) | Low molecular chondroitin sulfate oral preparation, preparation method thereof and use thereof | |
| CN101511170A (en) | Sublimable sustained release delivery system and method of making same | |
| JP4224866B2 (en) | Base with controlled dissolution time | |
| JP5367570B2 (en) | Lorazepam stabilization | |
| GB2352172A (en) | Orally administered dose unit comprising a drug with an outer coating of an enteric polymer, which allows co-administered food to separate from the dose unit | |
| CA1337274C (en) | Enteric film and preparation thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| ASS | Succession or assignment of patent right |
Owner name: SHENZHEN LISHILONG SCIENCE AND TECHNOLOGY CO., LTD Free format text: FORMER OWNER: SHANGHAI NISHENG BIOTECHNOLOGY CO., LTD. Effective date: 20100115 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20100115 Address after: Main building of science and Technology Innovation Park, the Peach Garden, Shenzhen, Baoan District 311 Applicant after: Shenzhen Lishilong Technology Co., Ltd. Address before: Lane 999, Lane 38, Hongmei Road, Shanghai, Minhang District 102 Applicant before: Nisheng Biology Science and Technology Co., Ltd., Shanghai |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20080924 |