CN1320887C - Methotrexate oral disintegrating tablet and its preparation method - Google Patents
Methotrexate oral disintegrating tablet and its preparation method Download PDFInfo
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- CN1320887C CN1320887C CNB2004100357797A CN200410035779A CN1320887C CN 1320887 C CN1320887 C CN 1320887C CN B2004100357797 A CNB2004100357797 A CN B2004100357797A CN 200410035779 A CN200410035779 A CN 200410035779A CN 1320887 C CN1320887 C CN 1320887C
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- methotrexate
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Abstract
The present invention relates to an orally disintegrating methotrexate tablet which can be rapidly disintegrated in the oral cavity without water. The orally disintegrating tablet is prepared by uniformly mixing methotrexate, sodium carboxymethyl starch, microcrystalline cellulose, mannitol and magnesium stearate which are respectively pulverized and screened with a screen of 100 meshes and adopting a powder direct compression process. The disintegrating time of the orally disintegrating tablet in the oral cavity is within 15 seconds, the disintegrating time of the orally disintegrating tablet in vitro is less than 1 minute, medical dissolution speed is high, bio utilization is high, and the dissolution of the orally disintegrating tablet in 15 minutes reaches more than 90.1% equal to the dissolution of the common tablet in 60 minutes.
Description
Affiliated technical field:
The present invention relates to contain the pharmaceutical composition of methotrexate, is the improvement technology about a kind of methotrexate oral formulations.
Technical background:
The history that methotrexate is used existing decades clinically, begin to be used for the treatment of leukemia and be used as antitumor drug, comprise various acute leukemia, particularly acute lymphoblastic leukemia, malignant lymphoma, non_hodgkin lymphoma and cutaneous T cell lymphoma, multiple bone marrow disease, incidence cancer, pulmonary carcinoma, various soft tissue sarcoma, psoriasis; Breast carcinoma, ovarian cancer, cervical cancer, malignant mole, chorionic epithelioma, carcinoma of testis etc.In recent years, methotrexate is widely used in the treatment of autoimmune diseasees such as activeness rheumatoid arthritis as a kind of immunosuppressant.
Methotrexate is insoluble in water, and bioavailability and external dissolution characteristic have certain dependency in its body.The methotrexate oral formulations that uses clinically at present is the methotrexate sheet, and its bioavailability is at 50mg/m
2Dosage is 20-50%, more heavy dose of (200mg/m
2) reduce to 25%.The reason that methotrexate conventional tablet bioavailability is lower shortcoming slow with its disintegration rate, that dissolution is low is relevant.
Summary of the invention:
The object of the present invention is to provide a kind of taking convenience, absorb the methotrexate orally disintegrating tablet preparation fast, that bioavailability is high.
For the medicine that is insoluble in water, bioavailability and external dissolution characteristic have certain dependency in its body.Because methotrexate is insoluble in water, therefore, the present invention promotes the absorption of human body to methotrexate to shorten the disintegration of tablet time, to improve its dissolution speed and start with, and makes methotrexate can reach effective blood drug concentration fast, onset rapidly.In addition, methotrexate is used for the chemotherapy of tumors process, the common untoward reaction of patient is vomiting, solution of the present invention is that methotrexate is mixed with a kind of methotrexate orally disintegrating tablet that does not need water to get final product rapid disintegrate in the oral cavity, both can accelerate dissolution rate, be applicable to the chemotherapy of tumors patient that water breakthrough is promptly vomitted again, and the patient under old people and the special environment that can not obtain water.
Oral cavity disintegration tablet is that a kind of water that do not need in the oral cavity can disintegrate or dissolved tablet.Do not need water when taking such preparation or only need use low amounts of water, also need not to chew, tablet places lingual surface to meet the rapid disintegrate of saliva, borrows swallowing act to go into the stomach onset.Methotrexate is made oral cavity disintegration tablet, disintegration time is obviously shortened, dissolution rate improves, and absorbs soon, and the bioavailability height improves the compliance of clinical application.
The technical essential of preparation oral cavity disintegration tablet is to make the quick disintegrate of tablet, has good mouthfeel again.
The characteristics of methotrexate in clinical use are that the dosage specification is less, and usual amounts is each oral 5～10mg, and 1 time on the one, the specification dosage of commercially available ordinary tablet is the 2.5mg/ sheet.Methotrexate is orange-yellow crystalline powder, and odorless, tasteless behind its micronization, there is no grittiness, no special odor and taste in the oral cavity.According to the characteristics of methotrexate raw material, the preparation technology of choice of powder direct compression process.
The main points that adopt direct powder compression to prepare tablet are to guarantee that the flowability and the compressibility of mixed-powder are good.Because the content of methotrexate in every is 2.5mg, little in the ratio that whole tablet Chinese traditional medicine accounts for, the flowability of raw material itself and compressibility are less to the influence of direct compression; And filler accounts for larger proportion, and the flowability of mixed-powder and compressibility depend mainly on the performance of filler.Therefore, select proper supplementary material kind and ratio for use, make the disintegration rate of oral cavity disintegration tablet fast, suitable hardness is arranged, preparation process is easy to large-scale production.
Oral cavity disintegration tablet of the present invention is made up of components such as methotrexate, disintegrating agent carboxymethyl base Starch Sodium, dry adhesive microcrystalline Cellulose, magnesium stearate lubricant and correctives mannitol.Its constituent content is by weight percentage: the methotrexate of 3.5-7.5wt%, the carboxymethyl starch sodium of 20.0-24.0wt%, the microcrystalline Cellulose of 55.0-65.0wt%, the magnesium stearate of 1.0-2.0wt%, the mannitol of 10.0-20.0wt%.
The disintegration of oral cavity disintegration tablet and disintegrating agent performance are closely related.Tablet why speed to collapse be because its disintegrating agent has water insoluble (or not exclusively water-soluble) and bibulous characteristics, disintegrating agent penetrates among the tablet hydrone by capillarity easily, suction back powder expands and does not dissolve, do not form colloid solution, be unlikely to hinder the continuation infiltration of hydrone, make the further disintegrate of tablet.The present invention is disintegrating agent with the carboxymethyl starch sodium.Its degree of exchange of the carboxymethyl starch sodium of selecting for use is generally about 0.3-0.5, and swellbility is 5ml/g, all can use as commercial goods Primojel, Explotab or DST etc.
Microcrystalline Cellulose is mobile and compressibility is good, is suitable for direct compression, plays a part dry adhesive in direct compression technology.Secondly, microcrystalline Cellulose also has good disintegration, also helps disintegrate in this product, but its swellbility lower (3.4ml/g), and along with the increase of microcrystalline cellulose cellulose content, is the trend of prolongation disintegration.Reason may be that variation has taken place the tablet internal structure, the mutual chimeric compact texture that formed of the particulate concaveconvex shape of microcrystalline Cellulose, and hole is difficult for by moistening tablet by compression failure.Microcrystalline Cellulose is the straight-chain polysaccharide that is made of pyranoid ring D-glucose, and its degree of polymerization is 200, and swellbility is 3.4ml/g, all can use as commercially available Avicel, PH-101, PH-102 etc.
Correctives can be selected mannitol for use, also can add aspartame, saccharin sodium, stevioside, essence etc.Mannitol is correctives and filler commonly used in the tablet, dissolving rapidly in the oral cavity, and heat absorption when dissolving, and cool taste is sweet and tasty.But the prescription screening data of this research show that along with the increasing of mannitol consumption, disintegration time increases, and by the mouthfeel of overall merit disintegration time, determines the optimum dose of mannitol.
Lubricant can be selected magnesium stearate for use, micropowder silica gel etc., and general usual amounts is 1-2%.
The present invention has done the selection test of disintegrating agent use amount, is the dry adhesive of direct compression with the microcrystalline Cellulose, according to data in literature, selects the amount ranges of 55-80%, selects the kind and the consumption of disintegrating agent on this basis.
Low-substituted hydroxypropyl cellulose and carboxymethyl starch sodium are excellent disintegrating agent, and have bibliographical information low-substituted hydroxypropyl methylcellulose can hide bad smell.The design of low-substituted hydroxypropyl cellulose and carboxymethyl starch sodium consumption in the scope of 15-30%, and is compared by measuring disintegration, and the consumption of EXPERIMENTAL DESIGN prescription sees Table 1, table 2.
With mannitol is correctives, according to mouthfeel and disintegration as judge index, further optimize technology.The consumption of EXPERIMENTAL DESIGN prescription sees Table 3.
Test method: the amount weighing supplementary material by the design prescription, sieve, mixing adopts direct powder compression to prepare test specimen, measures the disintegration time of quadrat sampling product everywhere respectively.
The assay method of disintegration is: add 37 ℃ ± 1 ℃ water 2ml in the 10ml graduated cylinder, get 1 oral cavity disintegration tablet, add in the entry, tablet should disintegrate rapidly in water, and the granule after the disintegrate should be able to be by 40 mesh sieves (internal diameter be 441um).6 of recheckings, the disintegrate situation of observing tablet, record complete disintegrate of tablet and granule are by the time of screen cloth.Test data with the results are shown in Table 1, table 2.
The screening of table 1 disintegrating agent (low-substituted hydroxypropyl cellulose) consumption
| The test lot number | 1 | 2 | 3 | 4 | 5 |
| Methotrexate (g) low-substituted hydroxypropyl cellulose (g) microcrystalline Cellulose (g) magnesium stearate (g) | 0.5 1.5 8 0.1 | 0.5 2.0 8 0.1 | 0.5 2.5 8 0.1 | 0.5 3.0 8 0.1 | 0.5 3.5 8 0.1 |
| Disintegration (second) | 78 | 72 | 71 | 68 | 75 |
The screening of table 2 disintegrating agent (carboxymethyl starch sodium) consumption
| The test lot number | 6 | 7 | 8 | 9 | 10 |
| Methotrexate (g) carboxymethyl starch sodium (g) microcrystalline Cellulose (g) magnesium stearate (g) | 0.5 1.5 8 0.1 | 0.5 2.0 8 0.1 | 0.5 2.5 8 0.1 | 0.5 3.0 8 0.1 | 0.5 3.5 8 0.1 |
| Disintegration (second) | 45 | 41 | 35 | 28 | 33 |
From table 1, table 2 as can be seen, low-substituted hydroxypropyl cellulose and carboxymethyl starch sodium compare, and carboxymethyl starch sodium is as disintegrating agent, and the disintegrating property of test lot number 9 is best.
For improving the mouthfeel of oral cavity disintegration tablet, intend adding mannitol as correctives.Based on test lot number 9, the mannitol of adding different amounts, test data and the results are shown in Table 3.
The screening of table 3 correctives (mannitol) consumption
| The test lot number | 11 | 12 | 13 | 14 | 15 |
| Methotrexate (g) carboxymethyl starch sodium (g) microcrystalline Cellulose (g) magnesium stearate (g) mannitol (g) | 0.5 3.0 8 0.1 1.0 | 0.5 3.0 8 0.1 1.5 | 0.5 3.0 8 0.1 2.0 | 0.5 3.0 8 0.1 2.5 | 0.5 3.0 8 0.1 3.0 |
| Disintegration (second) | 28 | 29 | 30 | 35 | 38 |
| Mouthfeel | No grittiness | No grittiness | No grittiness | No grittiness | No grittiness |
| Mouthfeel is general | Mouthfeel is general | Good mouthfeel | Good mouthfeel | Good mouthfeel |
As can be seen from Table 3, the increase of mannitol addition can improve mouthfeel, but also can prolong disintegration time.Comprehensive two kinds of factors are selected lot number 13 the bests, and its disintegration of the methotrexate orally disintegrating tablet that makes and mouthfeel all adhere to specification.Therefore the present invention is 20-24wt% by the component content of testing selected carboxymethyl starch sodium, and the component content of microcrystalline Cellulose is 55-65wt%.
In technique of direct powder compression, owing to directly carry out tabletting without the particulate process of preparation, the flowability of powder and compressibility are the indexs of outbalance, are related to the feasibility of carrying out suitability for industrialized production.If mixed-powder is mobile bad, can have influence on tabletting speed aborning, or the drawbacks such as tablet weight difference is big of compacting; If the compressibility of powder is bad, the tablet mechanical strength of making is not high, and is damaged easily in transportation and storage.In this research, for the flowability and the further checking of test of compressibility of mixed-powder, to guarantee the integrity of tablet in suitability for industrialized production product quality homogeneity, controllability and the Product transport.
Usually with angle of repose of powder as a kind of index of representing powder flowbility, the angle of repose of powder is more little, shows that the flowability of powder is good more.Be the further flowability of research powder, prepared 040101 batch sample, the amount of magnesium stearate in the lot number 13 is improved 1 times of (account for recipe quantity 1.5%) preparation 040102 batch sample according to lot number 13.Relatively the disintegration of 2 batch samples and the flowability of powder the results are shown in Table 4.
The test of table 42 batch sample physical performance index
| Lot number | 040101 | 040102 |
| Magnesium stearate consumption (%) mixed-powder disintegration time angle of repose (second) friability test (subtracting weight loss %) | 0.7 33.6° 30 1.1 | 1.5 29.8° 31 1.1 |
As can be seen from Table 4,040102 batch powder is less angle of repose, shows that mixed-powder is better mobile, and the disintegration time that makes tablet is also up to specification.
For verifying repeatability between each batch, according to 040102 batch prescription and tabletting pressure, prepare 040103,040104,040105 batch sample, measure the indexs such as flowability, compressibility and disintegration of material respectively, see Table 5.
The test of table 53 batch sample physical performance indexs
| Lot number | 040103 | 040104 | 040105 |
| Mixed-powder friability angle of repose test (subtracting weight loss %) disintegration time (second) | 29.2° 1.1 30 | 28.9° 1.2 31 | 29.5° 1.2 30 |
As can be seen from Table 5, the technology of direct powder compression is carried out the preparation of sample, and the mixed-powder of supplementary material has good flowability, the compressibility of mixed-powder is good, the tablet that is pressed under less pressure has good hardness, investigates through friability, subtracts weight loss at 1.1-1.2%.
For further verifying the flowability of material, measure the tablet weight variation of 3 batch samples, see Table 6.
Table 6 methotrexate orally disintegrating tablet weight differential check result
As can be seen from Table 6, the good fluidity of mixed-powder, good reproducibility between each batch, the suitability for industrialized production of suitable direct compression.
Be relatively assay method and the intraoral disintegration situation of disintegration, the oral cavity disintegration tablet of 3 lot numbers carried out volunteer's intraoral disintegration and test, with the assay method that contrasts external disintegration and the dependency of intraoral disintegration situation.
External disintegration of table 7 and intraoral disintegration time limit
| Lot number | Disintegration (second) | The intraoral disintegration time limit (second) |
| 040206 | 31.2±4.4 | 13.3±1.5 |
| 040207 | 30.5±3.9 | 12.7±1.5 |
| 040208 | 30.3±4.2 | 13.0±1.7 |
The result shows: three batch samples are disintegrate in 1 minute all, is equivalent in the oral cavity 15 seconds with interior disintegrate, may be because be disintegrate under the static environment external, and intraoral disintegration has due to the tongue motion.
For showing progressive of the present invention, we have also done the dissolution test of methotrexate orally disintegrating tablet of the present invention, and contrast with ordinary tablet.Ordinary tablet is selected from the methotrexate sheet that commercially available Shanghai Xinyi Pharmaceutical Co., Ltd produces, batch number: 020917.Assay method adopts two appendix XC of Chinese Pharmacopoeia version in 2000 three therapeutic methods of traditional Chinese medicine.Result of the test sees Table 8.
Table 8 methotrexate orally disintegrating tablet stripping uniformity test measurement result (%)
| Lot number | Time (minute) | 1 | 2 | 3 | 4 | 5 | 6 | On average ± SD (%) |
| 040206 | 5 10 20 30 45 60 | 94.7 93.9 93.5 94.1 93.3 93.3 | 92.5 91.5 91.1 91.7 91.5 92.1 | 92.3 91.1 90.7 91.1 91.1 91.5 | 94.3 93.9 94.3 93.9 93.9 93.5 | 94.3 93.1 92.1 92.5 91.7 91.1 | 93.3 94.3 92.1 92.1 92.5 92.3 | 93.6±1.02 92.9±1.36 92.3±1.38 92.6±1.20 92.3±1.10 92.3±0.93 |
| 040207 | 5 10 20 30 45 60 | 90.7 90.7 90.1 90.3 90.1 91.1 | 92.1 91.5 91.3 91.3 91.1 90.7 | 88.7 89.1 89.1 90.1 89.7 89.5 | 91.5 90.7 91.1 91.1 90.7 90.7 | 89.5 90.5 90.5 90.1 89.7 89.7 | 89.3 89.5 89.7 89.5 89.3 89.3 | 90.3±1.28 90.3±0.98 90.3±0.84 90.4±0.68 90.1±0.68 90.2±0.72 |
| 040208 | 5 10 20 30 45 60 | 89.3 90.5 90.3 90.5 90.3 90.1 | 91.7 92.1 91.7 91.7 91.5 91.1 | 88.9 90.1 89.7 90.1 89.9 90.1 | 90.1 88.9 88.9 88.7 88.7 88.9 | 89.7 91.7 91.7 91.5 91.3 91.1 | 91.1 90.5 90.7 90.7 90.5 90.7 | 90.1±1.07 90.6±1.15 90.5±1.11 90.5±1.08 90.4±1.02 90.3±0.83 |
| The methotrexate sheet | 5 10 20 30 45 60 | 13.3 25.7 41.8 68.9 83.2 86.7 | 15.2 24.0 40.8 64.4 81.6 88.3 | 23.4 31.9 48.5 68.1 85.9 88.1 | 17.0 30.1 43.0 65.5 84.0 85.9 | 15.6 29.9 45.0 65.2 86.7 87.5 | 20.2 28.1 42.4 63.0 85.0 88.5 | 17.4±3.71 28.3±2.97 43.6±2.75 65.8±2.24 84.4±1.86 87.5±1.02 |
According to the regulation of Chinese Pharmacopoeia, the qualified limit of ordinary tablet stripping is to reach 75% of labelled amount in 45 minutes.As can be seen from Table 3, the dissolution homogeneity of the present invention's three batch samples is good, individual variation is little in batch, favorable reproducibility between batch, the all more commercially available ordinary tablet of the dissolution of three batches of oral cavity disintegration tablets is obviously accelerated, dissolution promptly reached more than 90.1% in 5 minutes, had improved 72.7 % than the dissolution of ordinary tablet 5 minutes the time.So advantage of the present invention is clearly, its taking convenience, be that a kind of water that do not need in the oral cavity can disintegrate or dissolved tablet, absorb fast, bioavailability is high suitable with oral suspensions, for the old people of dysphagia with gulp down the cancer patient that water is promptly vomitted, and the patient under the special environment that can not obtain water is especially suitable.
The specific embodiment:
The invention will be further described with by way of example more below, provides implementation detail of the present invention, but be not to be intended to limit protection scope of the present invention.
Methotrexate, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate, mannitol are all crossed 100 mesh sieves.
Take by weighing methotrexate 2.5 gram, earlier with 15 gram carboxymethyl starch sodium with the equivalent method mixing that progressively increases, then add the abundant mixing of 40 gram microcrystalline Cellulose, then 10 gram mannitol and 1 gram magnesium stearate mixing successively.Detect the percentage composition of methotrexate in the mixed powder, after the calculating sheet was heavy, compacting in flakes.So can suppress 1000 methotrexate orally disintegrating tablets.
Its disintegration time is 25 seconds, and dissolution was 92.8% in 15 minutes.
The several examples of following reuse further specify the present invention.Following example is to produce the Formulation Example of 1000 oral cavity disintegration tablets.
Embodiment 1
Methotrexate 2.5g
Carboxymethyl starch sodium 13.5g
Microcrystalline Cellulose 42.5g
Mannitol 6.7g
Magnesium stearate 0.9g
Make 1000
Methotrexate, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate, mannitol are all crossed 100 mesh sieves.
Take by weighing methotrexate 2.5 gram, earlier with 14 gram carboxymethyl starch sodium with the equivalent method mixing that progressively increases, then add the abundant mixing of 42 gram microcrystalline Cellulose, then successively with 6.7 gram mannitol and 0.9 gram magnesium stearate mixing.Detect the percentage composition of methotrexate in the mixed powder, after the calculating sheet was heavy, compacting in flakes.So can suppress 1000 methotrexate orally disintegrating tablets.
Its disintegration time is 28 seconds, and dissolution was 91.9% in 15 minutes.
Embodiment 2
Methotrexate 5.0g
Carboxymethyl starch sodium 16g
Microcrystalline Cellulose 38g
Mannitol 7.8g
Magnesium stearate 1.2g
Make 1000
Methotrexate, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate, mannitol are all crossed 100 mesh sieves.
Take by weighing methotrexate 5.0 gram, earlier with 16 gram carboxymethyl starch sodium with the equivalent method mixing that progressively increases, then add the abundant mixing of 38 gram microcrystalline Cellulose, then 7.8 gram mannitol and 1.2 gram magnesium stearate mixings successively.Detect the percentage composition of methotrexate in the mixed powder, after the calculating sheet was heavy, compacting in flakes.So can suppress 1000 methotrexate orally disintegrating tablets.
Its disintegration time is 32 seconds, and dissolution was 93.1% in 15 minutes.
Embodiment 3
Methotrexate 2.5g
Carboxymethyl starch sodium 13.5g
Microcrystalline Cellulose 37.5g
Mannitol 13g
Magnesium stearate 1.1g
Make 1000
Methotrexate, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate, mannitol are all crossed 100 mesh sieves.
Take by weighing methotrexate 2.5 gram, earlier with 13.5 gram carboxymethyl starch sodium with the equivalent method mixing that progressively increases, then add the abundant mixing of 37.5 gram microcrystalline Cellulose, then 13 gram mannitol and 1.1 gram magnesium stearate mixings successively.Detect the percentage composition of methotrexate in the mixed powder, after the calculating sheet was heavy, compacting in flakes.So can suppress 1000 methotrexate orally disintegrating tablets.
Its disintegration time is 35 seconds, and dissolution was 92.9% in 15 minutes.
Claims (3)
1. methotrexate orally disintegrating tablet, form by methotrexate, dry adhesive microcrystalline Cellulose, magnesium stearate lubricant, disintegrating agent carboxymethyl base Starch Sodium and correctives mannitol, the composition content that it is characterized in that said oral cavity disintegration tablet, be by weight percentage: the methotrexate of 3.5-7.5wt%, the carboxymethyl starch sodium of 20.0-24.0wt%, the microcrystalline Cellulose of 55.0-65.0wt%, the magnesium stearate of 1.0-2.0wt%, the mannitol of 10.0-20.0wt%.
2. according to the described methotrexate orally disintegrating tablet of claim 1, it is characterized in that adopting direct powder compression.
3. according to the compound method of the described methotrexate orally disintegrating tablet of claim 1, it is characterized in that comprising following main preparation steps:
(1) methotrexate, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate, mannitol pulverize separately are crossed 100 mesh sieves;
(2) the first mixing with carboxymethyl starch sodium of methotrexate sieved, mixing with the microcrystalline Cellulose mixing, adds mannitol and magnesium stearate more again, mix homogeneously, and adjustment sheet is heavy to make the described methotrexate orally disintegrating tablet of claim 1 with the pressure tabletting.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022104022A1 (en) * | 2020-11-16 | 2022-05-19 | Orcosa Inc. | Rapidly infusing compositions with methotrexate and treatment methods |
| US11672761B2 (en) | 2020-11-16 | 2023-06-13 | Orcosa Inc. | Rapidly infusing platform and compositions for therapeutic treatment in humans |
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| CN103735501B (en) * | 2014-02-18 | 2016-01-13 | 长沙晶易医药科技有限公司 | Methotrexate chitosan thermosensitive hydrogel and application thereof |
| JP7060878B2 (en) * | 2016-07-27 | 2022-04-27 | 日本臓器製薬株式会社 | Film-coated tablets containing methotrexate |
| CN110269939A (en) * | 2019-03-12 | 2019-09-24 | 武汉愔紫生物科技有限公司 | A kind of drug, pharmaceutical composition, purposes and its application method for treating the protein mediated inflammation disease marker of fungus secretion |
| CN113209105A (en) * | 2021-05-27 | 2021-08-06 | 北京斯利安药业有限公司 | Pharmaceutical composition comprising folic acid and methotrexate |
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| JP2003321367A (en) * | 2002-04-26 | 2003-11-11 | Yuutoku Yakuhin Kogyo Kk | Ointment |
| WO2004002447A2 (en) * | 2002-06-26 | 2004-01-08 | Alza Corporation | Dosage forms for increasing the solubility and extending the release of drugs such as e.g. topiramate and phenyton |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022104022A1 (en) * | 2020-11-16 | 2022-05-19 | Orcosa Inc. | Rapidly infusing compositions with methotrexate and treatment methods |
| US11672761B2 (en) | 2020-11-16 | 2023-06-13 | Orcosa Inc. | Rapidly infusing platform and compositions for therapeutic treatment in humans |
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| CN1754538A (en) | 2006-04-05 |
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