CN103705490A - Slow-release preparation of ornithine aspartate and preparation process thereof - Google Patents
Slow-release preparation of ornithine aspartate and preparation process thereof Download PDFInfo
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Abstract
The invention provides a slow-release preparation of ornithine aspartate, the slow-release preparation comprises major components of the ornithine aspartate and an auxiliary additive, and controlled release of active ingredients in the preparation can be realized by the auxiliary additive. The preparation prepared into a capsule preparation formulation overcomes the defects that other ornithine aspartate preparations such as an injection are high in concentration, inconvenient to store and transport, and difficult to use for a patient by oneself, and the preparation has the advantages of convenience for middle and old age patients to take, quick absorption, high biological utilization rate and the like. The slow-release preparation of the ornithine aspartate is suitable for blood ammonia rising caused by acute and chronic liver diseases (such as various types of hepatitis, liver cirrhosis, fatty liver and post-hepatitis syndrome) and treatment of hepatic encephalopathy such as potential or attack-stage hepatic encephalopathy accompanying with or secondary with liver detoxification function damage (such as liver cirrhosis), and is especially suitable for the treatment of consciousness clouding state and other diseases in an early hepatic coma period and a hepatic coma period.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, a kind of prevention, treatment and protection that is applicable to hepatic encephalopathy is provided, particularly relate to a kind of aspartic acid ornithine slow releasing capsule dosage form.
Background technology
Hepatic encephalopathy (hepatic encephalopathy, HE) by serious hepatopathy, caused, the syndrome that the metabolism disorder of take is basic central nervous system dysfunction, clinical manifestation is disturbance of consciousness and behavioral disorder, is the common complication of serious hepatopathy and the cause of death.According to clinical manifestation, hepatic encephalopathy is divided into the fourth phase.First phase (prodromal period) take that slightly to sexually revise with behavioral disorder be feature, and symptom is not obvious and different is sometimes left in the basket.Second phase (precoma stage) take confusion of consciousness, sleep disorder, behavioral disorder as main.Three phases were lethargic stage, and the fourth phase is coma stage.Treatment of the present invention location, because acute and chronic hepatopathy is (as various hepatitis, liver cirrhosis, syndrome after fatty liver, hepatitis) blood ammonia causing raises and treatment hepatic encephalopathy, as occur together or be secondary to liver detoxification function impaired (as liver cirrhosis) potentiality or stage of attack hepatic encephalopathy, be particularly useful for treating the confusional state of early stage or hepatic coma phase of hepatic coma.
China Shi Yige hepatitis big country, only take Type B viral hepatitis as example, and its virus carrier just has 1.3 hundred million people, and existing patient more than 2,000 ten thousand, wherein transfers Chronic Liver sclerosis person to and account for 30%; Have report that Detection of Subclinical Hepatic Encephalopathy is added up interior, hepatic encephalopathy accounts for 70% of patients with cirrhosis.
Present Research to the Therapeutic Method of hepatic encephalopathy and medicine: many to hepatic encephalopathy Therapeutic Method at present, how according to the different phase of the different causes of disease and disease, to carry out Comprehensive Treatment clinically, to obtaining optimum curative effect.Now HE Therapeutic Method and medicine are in recent years summarized as follows:
Eliminate inducement, avoid excessive absorption albumen, prevention and treatment digestive tract hemorrhage, cause during digestive tract hemorrhage that Hypovolemia, intestinal produce ammonia and increase, and can bring out or increase the weight of HE.Avoid arranging in a large number potassium diuresis and put ascites.In addition, should reduce the medicine of vascular resistance in portal vein pressure, reduction Portal Vein Flow, reduction portal vein and liver, prevention and treatment esophageal varicosis and hemorrhage.
The poisonous substance that reduces enteral generates and absorbs, suppress intestinal bacteria growth, remove enteral food stagnation, hematocele or other nitrogen substances, with normal saline or weakly acidic solution cleansing enema, oral aperient is as lactulose, lactulose decomposes acetic acid reduction intestinal pH, the ammonia produced is combined with hydrion and generates ammonium ion, excretes, and reduces formation and the absorption of ammonia.Oral antibiotic can suppress intestinal bacteria, as metronidazole, neomycin, vancomycin.Oral neomycin or oral paromomycin, norvancomycin, be applicable to the bad person of renal function.Recently rifaximin is seldom more and more subject to clinician's favor because causing low drug resistance and adverse events, can be used as a line medication for the treatment of HE.Probiotic bacteria can regulating intestinal canal flora, suppresses urease-producing bacterial growth, promotes non-urease-producing bacterial growth, reduces the generation of ammonia, thereby reduces blood ammonia.Probiotic bacteria use aspect treatment HE is more extensive.
Improve nervous function medicine, the metabolism disorder of branched-chain amino acid correct amino acid, suppresses the formation of brain false neurotransmitter; Benzene phenodiazine receptor antagonist, flumazenil.Dopamine-receptor stimulant bromocriptine, has the effect of exciting postsynaptic dopamine receptor, and Nerve conduction is strengthened.
Other treatment method: 1) blood purification treatment, plasmapheresis is the method that HE is more ripe for the treatment of at present, can remove medium and the immune complex of poisoning by blood plasma element, antibody, activate immunity reaction.Its shortcoming is also obvious, easily occur irritated, infection and hemorrhage, blood calcium concentration reduces, retention of sodium and water, therefore do not advocate to use merely plasmapheresis.2) liver transplantation.Fetal stem cell transplanting, portosystemic shunt and obstruction, liver transplantation there is no at present other to be satisfied with chronic hepatopathys that Therapeutic Method reverses is a kind of generally acknowledged effective Therapeutic Method many, can fundamentally solve liver function and lose compensatory problem, thereby just starve just a series of complication, improve the quality of living, extend patient's life.But because it relates to, liver source, operation risk, immunosuppressant are used, economic dispatch is restricted this treatment application.3) other are suited the medicine to the illness and auxiliary treatment, comprise and correct water, electrolyte and acid base imbalance; Protect function of brain cell, prevent and treat cerebral edema; Keep respiratory passage unblocked; Hyperbaric oxygentherapy; Chinese medicine.
The deficiency that medicine exists at present: treat at present the more satisfactory medicine of hepatic encephalopathy or lactulose, newborn pears alcohol.The discomforts such as lactulose can produce abdominal distention, feels sick after taking, vomiting, lactulose is also bred intestinal bacillus perfringens, may be the reason that causes abdominal distention, and the too large long-term taking of sugariness is difficult for being accepted by patient in addition.Neomycin long-term taking, there is audition or renal function impairment in small number of patients, should not be over 1 month therefore take neomycin.Rifaximin is and the similar medicine of rifamycin, by the synthetic bacteriostasis that plays of RNA of anti-bacteria, can effectively suppress staphylococcus, enterococcus, streptococcic growth, but invalid to enterobacteria, simultaneously, antibiotic prolonged application has the danger that causes dysbacteriosis.Sodium glutamate is difficult for seeing through blood brain barrier, and sodium glutamate is alkaline medicine, can make blood pH value raise, and produces alkalosis, and sodium ion can increase the weight of edema, ascites and oliguria.Branched-chain amino acid is the imbalance that main aminoacid mixings liquid in theory can correct amino acid metabolism, suppresses the formation of brain central neurotransmitter, thereby improves HE symptom, current still disputable to the therapeutic effect of portal-systemic encephalopathy.It is better that benzodiazepine receptors antagonist has scholar to propose flumazenil treatment HE short term effect, and late result waits further confirmation, and Bolos intravenous administration has some patients were can cause slight and of short duration feeling sick, scheme.In addition, to the intelligence of hepatic encephalopathy without significantly improvement effect.Bromocriptine is a species specific dopamine receptor promoter, and someone thinks that this medicine is effective to the invalid chronic portal-systemic encephalopathy of internal medicine conventional therapy, but this conclusion is still disputable, can cause that in addition prolactin antagonist increases.
Aspartic acid ornithine can directly effectively reduce blood ammonia, as the drug of first choice of hepatic encephalopathy and prophylactic treatment.Generally improve the energy supply in hepatocyte, recover rapidly liver function, can reduce the transaminase of various chronic hepatopathys and the level of serum bilirubin, this product is natural amino acid composition, can improve tumor patient due to the caused various symptoms of negative nitrogen balance, improve patient for the tolerance of radiation and chemotherapy; Know and accumulate noxious substance in vivo, reduce hepatocellular damage, as tumor patient, accept the adjuvant drug of radiation and chemotherapy.But current existing preparation all cannot be realized controlled release or slow release, and for the ordinary preparation of aspartic acid ornithine, as injection, its specification is 5g:10ml, concentration is large, preserve and transportation inconvenient; When being used, patient patient oneself has any problem.
But can finely not realize the preparation of aspartic acid ornithine controllable release at present, in view of this, special proposition the present invention.
Summary of the invention
In order to realize better the controllable release to aspartic acid ornithine, the first object of the present invention is to provide a kind of aspartic acid ornithine slow releasing capsule dosage form.
For realizing the first object, the present invention adopts following technical scheme:
An aspartic acid ornithine slow releasing preparation, by weight, is prepared from by following crude drug:
Wherein, pastille label is prepared from by 85% alcoholic solution 90-100 part of 100 parts of aspartic acid ornithines, 158 parts of celphere and 5-10% polyvinylpyrrolidone.Preferred described slow releasing preparation by weight, is prepared from by following crude drug:
Wherein, pastille label is prepared from by 95 parts of 85% alcoholic solution of 100 parts of aspartic acid ornithines, 158 parts of celphere and 6% polyvinylpyrrolidone.
Above-mentioned slow-release material includes, but are not limited to ethyl cellulose, stearic acid, Eudragit(acrylic resin) one or more in RS100, Eudragit RL100, hydroxypropyl emthylcellulose, preferred, ethyl and stearic acid.
Selected plasticizer is triethyl citrate or PEG-4000, preferably PEG-4000.
Selected antiplastering aid is silicon dioxide, Pulvis Talci and/or magnesium stearate.
As a kind of preferred forms of the present invention, preferably by weight, by following crude drug, be prepared from:
Wherein, pastille label is prepared from by 95 parts of 85% alcoholic solution of 100 parts of aspartic acid ornithines, 158 parts of celphere and 6% polyvinylpyrrolidone.
Aspartic acid ornithine slow releasing preparation of the present invention, in the slow releasing preparation of per unit dosage, the content of aspartic acid ornithine is 0.1～1g, preferably 0.2-0.3g.
In order to obtain more preferably slow release effect, the preferred described slow releasing preparation of the present invention is capsule.
The second object of the present invention is to provide the preparation method of above-mentioned slow releasing preparation.
Aspartic acid ornithine slow releasing capsule of the present invention preparation be divided into two steps, the first step is that raw material fine powder is adhered on celphere by suitable binding agent, makes containing pill core, second step is to containing pill core bag extended release coatings film, controls principal agent and discharges.
Concrete preparation method is as follows:
(1) preparation is containing pill core: aspartic acid ornithine is crossed to 80 mesh sieves, and recipe quantity takes, after add celphere, spray is containing 85% alcoholic solution of PVP, pelletize; 40 ℃～50 ℃ oven dry, must contain pill core;
(2) prepare slow releasing preparation: recipe quantity takes step (1) gained containing pill core, spray into 95% ethanol of slow-release material, 40 ℃ of oven dry, granulate, the antiplastering aid and the plasticizer that add recipe quantity, 25 order granulate, mix homogeneously, measures intermediate content, after qualified, filled capsules, product inspection packing, obtains.
The present invention, by the optimization to the adjustment of preparation prescription and preparation method, has obtained a kind of novel formulation of the slow release of can realizing ideal.Aspartic acid ornithine slow releasing capsule of the present invention is taken twice every day, each one, compare with aspartic acid ornithine granule, its granule needs every day takes after mixing it with water three times, require patient compliance degree higher, and slow release formulation of the present invention can reach the requirement that 12 hours a time oral administration can meet blood drug level.The present invention compares with ornithine aspartate injection, due to the slow feature discharging of this dosage form, can continue release in 9 hours, thereby maintain blood drug level and longer action time comparatively stably, have advantages of that toxic and side effects is little, it is convenient to use, can also obtain Social benefit and economic benefit widely simultaneously.
accompanying drawing explanation
Fig. 1 is the cumulative in vitro releasing curve diagram of prescription A;
Fig. 2 is the cumulative in vitro releasing curve diagram of prescription B;
Fig. 3 is the cumulative in vitro releasing curve diagram of prescription C;
Fig. 4 is the cumulative in vitro releasing curve diagram of prescription D;
Fig. 5 is the cumulative in vitro releasing curve diagram of prescription E;
Fig. 6 is the cumulative in vitro releasing curve diagram of prescription F;
Fig. 7 is the cumulative in vitro releasing curve diagram of prescription G;
Fig. 8 is the cumulative in vitro releasing curve diagram of prescription H.
the specific embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
In following examples, chemical reagent used is commercial goods.
Embodiment 1
(1) contain the preparation of pill core
Aspartic acid ornithine 200g
Celphere 316g
6%PVP solution (solvent is 85% ethanol) 190g
Preparation technology:
Aspartic acid ornithine is crossed to 80 mesh sieves, and recipe quantity takes, and pours in granulation coating machine hopper, sets into wind pressure and rotary speed, then pours celphere into, pelletize.Spray 6%PVP solution (solvent is 85% ethanol), 40 ℃ of oven dry, pelletize finishes, discharging 500g.
(1) contain the preparation of pill core
Aspartic acid ornithine 200g
Celphere 316g
6%PVP solution (solvent is 85% ethanol) 180g
Preparation technology:
Aspartic acid ornithine is crossed to 80 mesh sieves, and recipe quantity takes, and pours in granulation coating machine hopper, sets into wind pressure and rotary speed, then pours celphere into, pelletize.Spray 6%PVP solution (solvent is 85% ethanol), 50 ℃ of oven dry, pelletize finishes, discharging 495g.
Embodiment 3
(1) contain the preparation of pill core
Aspartic acid ornithine 200g
Celphere 316g
6%PVP solution (solvent is 85% ethanol) 200g
Preparation technology:
Aspartic acid ornithine is crossed to 80 mesh sieves, and recipe quantity takes, and pours in granulation coating machine hopper, sets into wind pressure and rotary speed, then pours celphere into, spray 6%PVP solution (solvent is 85% ethanol), pelletize.45 ℃ of oven dry, pelletize finishes, discharging 508g.
Slow releasing preparation prescription screening test (determining best slow releasing agent and plasticizer kind and quantity):
Prescription A:
Preparation technology: recipe quantity takes containing pill core, pours in granulation coating machine hopper, sets into wind pressure and rotary speed.Spray into Eudragit(acrylic resin) RS100 and stearic 95% ethanol, 40 ℃ of oven dry, discharging 510g, 20 orders are granulated, the silicon dioxide and the PEG-4000 that add recipe quantity, 25 order granulate, mix homogeneously, measures intermediate content, after qualified, filled capsules, product inspection packing.
Prescription B
Preparation technology: recipe quantity takes containing pill core, pours in granulation coating machine hopper, sets into wind pressure and rotary speed.Spray into Eudragit RL100 and stearic 95% ethanol, 40 ℃ of oven dry, discharging 504g, 20 orders are granulated, the silicon dioxide and the PEG-4000 that add recipe quantity, 25 order granulate, mix homogeneously, measures intermediate content, after qualified, filled capsules, product inspection packing.
Prescription C
Preparation technology: recipe quantity takes containing pill core, pours in granulation coating machine hopper, sets into wind pressure and rotary speed.Spray into hydroxypropyl emthylcellulose and stearic 95% ethanol, 40 ℃ of oven dry, discharging 515g, 20 orders are granulated, the silicon dioxide and the PEG-4000 that add recipe quantity, 25 order granulate, mix homogeneously, measures intermediate content, after qualified, filled capsules, product inspection packing.
Prescription D
Preparation technology: recipe quantity takes containing pill core, pours in granulation coating machine hopper, sets into wind pressure and rotary speed.Spray into ethyl cellulose and stearic 95% ethanol, 40 ℃ of oven dry, discharging 510g, 20 orders are granulated, and add silicon dioxide and the PEG-4000 of recipe quantity, 25 order granulate, mix homogeneously, measures intermediate content, qualified after, filled capsules, product inspection packing.
Prescription E
Preparation technology is with prescription A.
Prescription F
Preparation technology is with prescription B.
Prescription G
Preparation technology is with prescription C.
Prescription H
Preparation technology is with prescription D.
Aspartic acid ornithine slow releasing capsule dissolution determination.
Aspartic acid ornithine slow releasing capsule (prescription A-G), its extracorporeal releasing experiment method is as follows: get this product according to drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2010), utilize dissolution determination device (two appendix XC first methods of Chinese Pharmacopoeia version in 2010), take hydrochloric acid solution (9 → 1000) 1000 is solvent, rotating speed 50 turns, in accordance with the law operation.At 1,48 lab scale, get respectively solution 100ml(the instant equivalent solvent that supplements), filter, precision measures subsequent filtrate 3ml, put in 50ml volumetric flask, with same solvent dilution to scale, as need testing solution; Separately learning from else's experience 105 ℃, it is appropriate, accurately weighed to be dried to the aspartic acid ornithine reference substance of constant weight, add that hydrochloric acid solution (9 → 1000) dissolves and quantitatively dilution make every 1ml containing the solution of 7.5 μ g, in contrast product solution.Respectively according to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2010), at the wavelength of 205nm, go out to measure the trap of need testing solution and reference substance solution, according to external standard method, calculate each test sample the burst size of 1,4,8 hour, desirable burst size preferably can reach respectively the more than 15%～35%, 45%～75% and 85% of labelled amount at 1,4,8 hour.Concrete testing result refers to table 1-8 and Fig. 1-8.
Table 1 prescription A cumulative in vitro release
Table 2 prescription B cumulative in vitro release
Table 3 prescription C cumulative in vitro release
Table 4 prescription D cumulative in vitro release
Table 5 prescription E cumulative in vitro release
Table 6 prescription F cumulative in vitro release
Table 7 prescription G cumulative in vitro release
Table 8 prescription H cumulative in vitro release
The aspartic acid ornithine preparation of above-mentioned prescription has all possessed comparatively desirable cumulative in vitro release, can effectively be applied to clinical treatment.Yet in order to realize more preferably drug release, maintain blood drug level and longer action time comparatively stably, inventor on the basis of above-mentioned test, further determined following preferred forms for the preparation of the present invention expect slow releasing preparation:
The embodiment 4(D that writes out a prescription):
Preparation technology: recipe quantity takes containing pill core (embodiment 1-3 any one is prepared, lower same), pours in granulation coating machine hopper, sets into wind pressure and rotary speed.Spray into ethyl cellulose and stearic 95% ethanol, 40 ℃ of oven dry, discharging 510g, 20 orders are granulated, and add silicon dioxide and the PEG-4000 of recipe quantity, 25 order granulate, mix homogeneously, measures intermediate content, qualified after, filled capsules, product inspection packing.The present embodiment gained capsule the burst size of 1,4,8 hour in Table 4.
Embodiment 5:
Preparation technology: recipe quantity takes containing pill core, pours in granulation coating machine hopper, sets into wind pressure and rotary speed.Spray into ethyl cellulose and stearic 95% ethanol, 40 ℃ of oven dry, discharging 502.4g, 20 orders are granulated, the silicon dioxide and the PEG-4000 that add recipe quantity, 25 order granulate, mix homogeneously, measures intermediate content, after qualified, filled capsules, product inspection packing.The present embodiment gained capsule is respectively 19%, 52% and 87% of labelled amount the burst size of 1,4,8 hour.
Embodiment 6:
Preparation technology: recipe quantity takes containing pill core, pours in granulation coating machine hopper, sets into wind pressure and rotary speed.Spray into ethyl cellulose and stearic 95% ethanol, 40 ℃ of oven dry, discharging 507.8g, 20 orders are granulated, the silicon dioxide and the PEG-4000 that add recipe quantity, 25 order granulate, mix homogeneously, measures intermediate content, after qualified, filled capsules, product inspection packing.The present embodiment gained capsule is respectively 22%, 52% and 90% of labelled amount the burst size of 1,4,8 hour.
Embodiment 7:
Preparation technology: recipe quantity takes containing pill core, pours in granulation coating machine hopper, sets into wind pressure and rotary speed.Spray into ethyl cellulose and stearic 95% ethanol, 40 ℃ of oven dry, discharging 512.8g, 20 orders are granulated, the silicon dioxide and the PEG-4000 that add recipe quantity, 25 order granulate, mix homogeneously, measures intermediate content, after qualified, filled capsules, product inspection packing.The present embodiment gained capsule is respectively 21%, 55% and 89% of labelled amount the burst size of 1,4,8 hour.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements, all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (9)
1. an aspartic acid ornithine slow releasing preparation, is characterized in that, by weight, by following crude drug, is prepared from:
Wherein, pastille label is prepared from by 85% alcoholic solution 90-100 part of 100 parts of aspartic acid ornithines, 158 parts of celphere and 5-10% polyvinylpyrrolidone.
2. aspartic acid ornithine slow releasing preparation as claimed in claim 1, is characterized in that, by weight, by following crude drug, is prepared from:
Wherein, pastille label is prepared from by 95 parts of 85% alcoholic solution of 100 parts of aspartic acid ornithines, 158 parts of celphere and 6% polyvinylpyrrolidone.
3. aspartic acid ornithine slow releasing preparation as claimed in claim 1 or 2, it is characterized in that, described slow-release material is one or more in ethyl cellulose, stearic acid, Eudragit acrylic resin RS100, Eudragit RL100 or hydroxypropyl emthylcellulose, preferred, ethyl and stearic acid.
4. aspartic acid ornithine slow releasing preparation as claimed in claim 1 or 2, is characterized in that, described plasticizer is triethyl citrate or PEG-4000, preferably Macrogol 4000.
5. aspartic acid ornithine slow releasing preparation as claimed in claim 1 or 2, is characterized in that, described antiplastering aid is silicon dioxide, Pulvis Talci and/or magnesium stearate, preferably silicon dioxide.
6. aspartic acid ornithine slow releasing preparation as claimed in claim 1 or 2, is characterized in that, by weight, by following crude drug, is prepared from:
Wherein, pastille label is prepared from by 95 parts of 85% alcoholic solution of 100 parts of aspartic acid ornithines, 158 parts of celphere and 6% polyvinylpyrrolidone.
7. aspartic acid ornithine slow releasing preparation as claimed in claim 1 or 2, is characterized in that, in the slow releasing preparation of per unit dosage, the content of aspartic acid ornithine is 0.1～1g.
8. aspartic acid ornithine slow releasing preparation as claimed in claim 1 or 2, is characterized in that, described slow releasing preparation is capsule.
9. the preparation method of aspartic acid ornithine slow releasing preparation described in claim 8, is characterized in that: comprising:
(1) preparation is containing pill core: aspartic acid ornithine is crossed to 80 mesh sieves, and recipe quantity takes, after add celphere, spray is containing 85% alcoholic solution of PVP, pelletize; 40 ℃～50 ℃ oven dry, must contain pill core;
(2) prepare slow releasing preparation: recipe quantity takes step (1) gained containing pill core, spray into 95% ethanol of slow-release material, 40 ℃ of oven dry, granulate, the plasticizer and the antiplastering aid that add recipe quantity, 25 order granulate, mix homogeneously, measures intermediate content, after qualified, filled capsules, product inspection packing, obtains.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108366983A (en) * | 2015-11-13 | 2018-08-03 | 欧塞拉治疗有限公司 | L-ornithine phenyl acetate preparation |
| CN108524453A (en) * | 2018-07-05 | 2018-09-14 | 扬子江药业集团广州海瑞药业有限公司 | A kind of pharmaceutical composition of aspartic acid ornithine |
| CN113209048A (en) * | 2021-04-16 | 2021-08-06 | 江苏大学 | Ornithine aspartate sustained-release pellet and preparation process thereof |
| US11219611B2 (en) | 2015-11-13 | 2022-01-11 | Ocera Therapeutics, Inc. | Formulations of L-ornithine phenylacetate |
| US11266620B2 (en) | 2009-06-08 | 2022-03-08 | Ucl Business Ltd | Treatment of portal hypertension and restoration of liver function using L-ornithine phenylacetate |
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| CN1887278A (en) * | 2006-07-25 | 2007-01-03 | 山东省医药工业研究所 | Slow released doxazosin mesilate capsule and its prepn process |
| CN103239434A (en) * | 2012-12-26 | 2013-08-14 | 辽宁亿灵科创生物医药科技有限公司 | Ornithine aspartate composition |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1887278A (en) * | 2006-07-25 | 2007-01-03 | 山东省医药工业研究所 | Slow released doxazosin mesilate capsule and its prepn process |
| CN103239434A (en) * | 2012-12-26 | 2013-08-14 | 辽宁亿灵科创生物医药科技有限公司 | Ornithine aspartate composition |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11266620B2 (en) | 2009-06-08 | 2022-03-08 | Ucl Business Ltd | Treatment of portal hypertension and restoration of liver function using L-ornithine phenylacetate |
| CN108366983A (en) * | 2015-11-13 | 2018-08-03 | 欧塞拉治疗有限公司 | L-ornithine phenyl acetate preparation |
| US11219611B2 (en) | 2015-11-13 | 2022-01-11 | Ocera Therapeutics, Inc. | Formulations of L-ornithine phenylacetate |
| CN108524453A (en) * | 2018-07-05 | 2018-09-14 | 扬子江药业集团广州海瑞药业有限公司 | A kind of pharmaceutical composition of aspartic acid ornithine |
| CN113209048A (en) * | 2021-04-16 | 2021-08-06 | 江苏大学 | Ornithine aspartate sustained-release pellet and preparation process thereof |
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| CN103705490B (en) | 2016-08-17 |
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