KR101003890B1 - Composition of docetaxel-loaded thermosensitive liquid suppository for rectal administration - Google Patents
Composition of docetaxel-loaded thermosensitive liquid suppository for rectal administration Download PDFInfo
- Publication number
- KR101003890B1 KR101003890B1 KR1020100034417A KR20100034417A KR101003890B1 KR 101003890 B1 KR101003890 B1 KR 101003890B1 KR 1020100034417 A KR1020100034417 A KR 1020100034417A KR 20100034417 A KR20100034417 A KR 20100034417A KR 101003890 B1 KR101003890 B1 KR 101003890B1
- Authority
- KR
- South Korea
- Prior art keywords
- docetaxel
- liquid suppository
- administration
- composition
- rectal administration
- Prior art date
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
Abstract
Description
The present invention relates to a new docetaxel dosage formulation, which is substantially applicable, to a docetaxel-containing thermosensitive liquid suppository for rectal administration, which is liquid at room temperature and has a property of forming a gel in the body and adhering to the mucosa.
In the case of docetaxel, an active ingredient of the present invention, an existing product is provided with an injection called Taxotere® (Taxotere®; Sanofiaventis), which is a solubilized formulation using polysorbate 80 together with ethanol. infusion), but has the disadvantage of causing side effects such as hypersensitivity reactions when administered to patients (Engels et al., Anticancer Drugs, 18 (2), 95-103 (2007); Sparreboom, et. al., Anticancer Drugs. 9 (1), 1-17 (1998).
In addition, oral administration of docetaxel is almost impossible due to CYP and P-GP inhibition and very low bioavailability (Woo et al., Pharm. Res., 20 (1), 24-). 30, (2003). Therefore, in order to increase the solubility and absorption of docetaxel, docetaxel is added to a polymer such as albumin to synthesize a polymer medicine (Musumeci et al., Int. J. Pharm., 325, 172-179 (2008)), attempts to cause glycosylation or ON intramolecular acylation (Schellens et al., Eur. J. Pharm. Sci., 12, 103-110 (2000)), or polysorbate 80 ( Gao et al., Drug Dev. Ind. Pharm., 34 (11), 1227-1237 (2008)), polysaccharides (Henni-Silhadi et al., Pharm. Res., 24 (12), 2317-2326 (2008)) and polosamers (Elsabahy et. al., Biomacromolecules, 8 (7), 2250-2257 (2007)) to form micelles or emulsions with surfactants, or poloxamers (Chen et al., Drug Dev. Ind. Pharm., 34 (6), 588-594 (2008)), polylactic-glycolic acid (Le Garrec et al., J. Control. Rel., 99 (1), 83-101 (2004)) and phospholipids (Straubinger et al., Methods) Enzymol., 391, 97-117 (2005)) and the like and solid dispersions such as liposomes And microcapsules (Musumeci et al., Int. J. Pharm., 325, 172-179 (2008); Schellens et al., Eur. J. Pharm. Sci., 12, 103-110 (2000) Woo et al., Pharm.Res., 20 (1), 24-30, (2003)) Although studies have been reported to develop oral or injectable drugs, there have been no satisfactory results and so far docetaxel-containing suppository products. Was not reported.
On the other hand, the conventional suppository system is a solid suppository that is solid at room temperature and melts or softens in the body to release an active ingredient because polyglycol or witepsol is used as a base. Suppositories have been used in the formulation of analgesic antipyretics, anesthetics, and hemorrhoids treatments because active ingredients are absorbed without first-passing effects in the gastrointestinal tract and liver and can also resolve patient discomfort, such as pain caused by injection. However, since these solid suppositories are solid at room temperature, patients feel foreign object and rejection when administered, and there is a risk of first passing effect due to colon peristalsis of the large intestine at the rectum after administration. There are also difficulties in the development of pharmaceutical preparations due to manufacturing difficulties (Huang et al., Yakuzaigaku , 47, 42-48 (1987)).
Therefore, to solve this problem, a new type of suppository composition called liquid suppository has been developed that is liquid at room temperature and forms gel in the body. This liquid suppository is based on gelling temperature of 30 ~ 36 ℃ using two or more poloxamers as a base, and by adding carbopol, polycarbophil, or sodium alginate, which have bioadhesive polymers, to have proper gel strength and bioadhesive power. It is easy to administer and adheres to the rectal mucosa after administration, so that it does not escape extracorporeally and enters the colon end (Choi et al., Int . J. Pharm ., 165, 33-44 (1998); Choi et al., Int . J. Pharm ., 190, 13-19 (1999); Choi et al., Int . J. Pharm ., 165, 23-32 (1998). In addition, this liquid suppository is easier to manufacture than conventional suppositories, such as not undergoing a melting step during preparation, and the active ingredients of acetaminophen, propranolol, diclofenac sodium salt, insulin, and prostaglandin E1 are applied to the liquid suppository in vivo. The utilization rate was increased [Korean Patent Application Publication Nos. 96-4566, 96-7637, 96-7638, PCT / KR97 / 0032, PCT / KR97 / 0042].
However, when the existing liquid suppository system is applied to the docetaxel as an active ingredient, its solubility is not increased, so that it is difficult to homogenize the formulation and its bioavailability is low, so that it cannot be applied as a practical formulation. In addition, bioadhesive polymers such as carbopol, polycarbophil or sodium alginate, which are used as gel strength and bioadhesive modifiers, take a long time to swell during manufacture, and especially when added together with docetaxel, an active ingredient, cause substantial phase separation. The preparation of possible formulations is not possible.
Thus, the new rectal solution that eliminates the risk of administration of the existing docetaxel injection and prevents phase separation of the existing liquid suppository system, as well as the convenience and efficacy of the administration of the existing suppository, is easy to manufacture, and the solubility of the docetaxel that is not easily dissolved in water is increased. There is an urgent need for the development of a washing-cell-containing temperature sensitive liquid suppository.
The object of the present invention,
Eliminate the risk of administration of injectables, the only existing formulation of docetaxel,
It solves the problem of docetaxel's pharmacological properties that are inhibited by CYP and P-GP during oral administration, resulting in extremely low bioavailability.
It solved the problem that the first time avoidance effect could not be properly obtained by transitioning to the colon terminal after administration, which is a disadvantage of the existing suppository,
Not only can the convenience of administration be obtained,
Phase separation does not occur when applied to the existing liquid suppository system, which is easy to manufacture and increases the solubility of poorly soluble docetaxel, thereby preventing precipitation.
Finally, there is provided a docetaxel-containing thermosensitive liquid suppository for rectal administration which can exhibit applicable bioavailability as a practical formulation.
Through the following specific aspects of the present invention it was possible to achieve the above object:
(1) 25 to 35% by weight of poloxamer, 2 to 10% by weight of polysorbate 80, 54 to 72.99% by weight of water and 0.01 to 1% by weight of docetaxel as an active ingredient,
Docetaxel-containing thermosensitive liquid suppository composition for rectal administration, characterized in that the gelation temperature is 30 ~ 36 ℃; or
(2) The docetaxel-containing thermosensitive liquid for rectal administration according to (1), wherein the poloxamer is a mixture of two or more selected from the group consisting of P 124, P 188, P 237, P 338, and P 407. Suppository composition.
Docetaxel-containing temperature sensitive liquid suppository composition for rectal administration according to the present invention,
Unlike the injection of Docetaxel, which is the only existing formulation, the introduction of the liquid suppository system not only eliminates the risk of administration but also provides convenience of administration.
Unlike oral administration, it is not inhibited by CYP and P-GP
Unlike the existing suppository system, it has the proper bioadhesive power and does not migrate to the end of the colon, so that the first pass avoidance effect can be obtained.
Unlike the existing liquid suppository system, it achieves perfect solubilization of poorly soluble docetaxel, so that no precipitate is formed and no phase separation occurs, so that a homogeneous and stable formulation can be obtained.
Finally, an absolute bioavailability of 29% was achieved, which is a value representing the bioavailability applicable as a practical formulation, unlike oral formulations.
Therefore, the composition of the present invention is expected to make a significant contribution to patients and medical staff requiring docetaxel administration by providing new, safe, convenient and effective dosage forms of docetaxel.
1 is an example of the results measured using a viscometer to see the gel time and gel strength. (Solid line, Example 2; short dashed line, Example 3; long dashed line, Example 1)
Figure 2 shows a device for measuring bio-adhesion produced by itself. (A, self-made two-handed scale; B, weight; C, vial; D, liquid suppository; E, rat mucosal tissue; F, jockey)
Figure 3 shows the blood concentration after rectal administration of the docetaxel-containing temperature-sensitive liquid suppository composition for rectal administration, oral administration of the docetaxel solution and intravenous administration of the docetaxel solution to the animal. (●, control group administered with docetaxel solution; ▼, control group administered orally with docetaxel solution; ○, Example 1 rectal administration group)
Referring to each composition component contained in the docetaxel-containing temperature sensitive liquid suppository composition for rectal administration according to the present invention in more detail as follows.
Poloxamers contained as a base in the docetaxel-containing thermosensitive liquid suppository composition for rectal administration according to the present invention are known to not cause damage to biological mucosa. In the present invention, a mixture of two or more selected from the group consisting of P 124, P 188, P 237, P 338 and P 407 is selected from commercially available poloxamers. The poloxamer base is contained in an amount of 25 to 35% by weight in the composition of the present invention, and the poloxamer base is preferably configured such that the gelation temperature of the composition of the present invention is maintained in the range of 30 to 36 ℃. If the gelation temperature is less than 30 ℃ the liquid suppository for rectal administration at room temperature becomes a solid phase, it is difficult to administer rectal, when it exceeds 36 ℃ because it becomes liquid in the body there is a possibility to escape out of the body. In addition, when the poloxamer base is less than 25% by weight in the composition of the present invention, the gelation temperature of the present invention is less than 30 ℃ exhibits a problem or docetaxel as an active ingredient is not completely solubilized and precipitates are formed. The problem is shown.
In the docetaxel-containing thermosensitive liquid suppository composition for rectal administration according to the present invention, polysorbate 80 used to increase the solubility of docetaxel is contained in an amount of 2 to 10% by weight. The amount of docetaxel that can be dissolved is determined by the weight of polysorbate 80. If the content of polysorbate 80 is less than 2% by weight, there is a problem that cannot be dissolved by the amount of docetaxel, which is the object of the present invention, and when it exceeds 10% by weight, docetaxel may be dissolved more but shows a very strong gel strength. Due to its strong viscosity in production, it is difficult to manufacture, it is difficult to administer, and there is a risk of damaging the rectal mucosa.
The method of formulating the docetaxel-containing thermosensitive liquid suppository composition for rectal administration according to the present invention is well known to those skilled in the art, and includes a conventional excipient and diluent including conventional gelling temperature and gel strength modifier, and the like. It may be prepared in the form.
The docetaxel-containing thermosensitive liquid suppository composition for rectal administration according to the present invention has a gelation temperature of 30 to 36 ° C. and has an appropriate gel strength and bioadhesive power, so that it is liquid at room temperature and forms a gel phase in the body for easy administration. It is not attached to the rectal mucosa and does not escape to the outside and does not migrate to the end of the colon.
Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited by the following Examples.
Example 1 to 8 and Comparative example 1 to 7
Polysorbate 80 in which the active ingredient was dissolved in the composition as shown in Table 1 and Table 2 was added to water at room temperature, and then dissolved by adding poloxamer at 4 ° C. The solution was left in the refrigerator for one day to remove bubbles to prepare a docetaxel-containing temperature sensitive liquid suppository composition for rectal administration.
As a result of observation after 1 day, docetaxel was completely dissolved in transparent liquid suppositories in Examples 1 to 8 and Comparative Examples 4 to 7, but as in Comparative Examples 1 to 2, polysorbate 80 was used for rectal administration of the present invention. When less than 2% by weight in the liquid suppository composition, docetaxel, an active ingredient, did not dissolve and showed a tendency to precipitate. In addition, as in the case of Comparative Example 3, even when poloxamer is less than 25% by weight in the rectal liquid suppository composition of the present invention showed a tendency to precipitate without melting. However, as in the case of Examples 1 to 8 and Comparative Examples 5 to 7, when the polysorbate 80 and poloxamer are 2% by weight and 25% by weight or more in the liquid suppository composition for rectal administration of the present invention, Docetaxel was completely dissolved in the liquid suppository composition. In the case of Comparative Example 4, the poloxamer content was slightly insufficient as 24 wt%, but the polysorbate 80 content was sufficient as 10 wt%, so that docetaxel was completely dissolved.
Experimental Example One : Gelation temperature
2 g of each of Examples 1 to 8 and Comparative Examples 4 to 7 prepared above were put together with a magnetic bar in a 10 ml vial container, and placed in a thermostat at 4 ° C., and then a digital thermometer was inserted into the sample so as not to contact the magnetic bar. The temperature at which the magnetic bar completely stopped was raised to a gelation temperature while the temperature was increased at a rate of 1 ° C./min while stirring at a constant speed.
As in Examples 1 to 8 of Table 3, when the docetaxel-containing temperature sensitive liquid suppository composition for rectal administration of the present invention is 10 wt% or less of polysorbate 80 and 25 to 35 wt% of poloxamer, the gelation temperature is 30 to 36 ° C. In consideration of the fact that the liquid suppository for rectal administration including docetaxel has been found to be easy to manufacture and administer because of the liquid state at room temperature and to immediately form a gel in the body. However, as in Comparative Examples 5 to 7, when the polysorbate 80 in the rectal liquid suppository composition of the present invention is more than 10% by weight or poloxamer is more than 35% by weight, the gelation temperature is less than 30 ℃ liquid state at room temperature The administration was inconvenient because of the viscous gel state. In addition, as in Comparative Example 4, when the poloxamer is less than 25% by weight in the liquid suppository composition for rectal administration of the present invention, the gelation temperature is higher than 36 ° C. to maintain the same liquid state as when the gel is not formed in the body. Indicates a tendency.
Experimental Example 2 : Gel time
Gelation time was measured using a Physica MCR 301 viscometer. The temperature was fixed at 36 ° C. and the shear rate [d (gamma) / dt] was set to 100 1 / s and measured for 40 minutes. An example of the measurement result is shown in FIG. 1. When the viscosity of the liquid suppository exceeded 4 Pas, it was judged to be gelation, and the time at that time was taken as the gelation time.
Considering that the gelation time of Examples 1 to 8 is 4-7 minutes, as shown in Table 4, the new rectal docetaxel liquid suppository of the present invention using polysorbate 80 can be prevented from gelling rapidly after administration. And it was confirmed that the drug can be efficiently absorbed.
Experimental Example 3: Gel strength
Gelation time was measured using a Physica MCR 301 viscometer. The temperature was fixed at 36 ° C. and the shear rate [d (gamma) / dt] was set to 100 1 / s and measured for 40 minutes. An example of the measurement result is shown in FIG. 1. After the viscosity of the liquid suppository reached the highest point, the viscosity when the viscosity was maintained for at least 10 minutes was measured by gel strength.
Considering that the gel strengths of Examples 1 to 8 correspond to 8-15 Pas, which is an appropriate numerical range as shown in Table 5, the new rectal tocetaxel liquid suppository prepared with polysorbate 80 was administered. Afterwards it turned out that it did not get out of the body.
Experimental Example 4: bioadhesion test
Two vials are settled in the bioadhesion measuring apparatus as shown in FIG. 2, and the rectal mucosa of the rabbit is attached to both vials, and about 0.05 g of Examples 1 to 8 are inserted between the two rectal mucosa, and then the weights are sequentially placed. The bioadhesive force was measured by converting the weight of the two vials from each other into the force per unit area. Considering that the bioadhesion of Examples 1 to 8 corresponds to an appropriate value (10 to 50 × 10 2 dyne / cm 2 ), as shown in Table 6, the new rectal docetaxel liquid suppository of the present invention using polysorbate 80 is used. It was found that after administration, it adhered to the rectal mucosa and did not escape out of the body and did not migrate to the end of the colon.
Experimental Example 5: animal experiment
Five 250 ± 20 g Sprague-Dawley male rats were fasted for 24-36 hours before the experiment, and Example 1 of Table 1 was inserted by 2 ml / kg (5 mg / kg of docetaxel) near the inner 4 cm of the rectum. . At a given time, 0.2 ml of blood was collected through the right femoral artery and 1.5 ml of acetonitrile and 50 µl of propylparaben (5 µg / ml, acetonitrile) were added to the plasma (150 µl) obtained by centrifugation. Centrifuged at 12,000 g for 8 minutes, the protein was precipitated, the supernatant was taken and evaporated for 3 hours and then dissolved in 100 [mu] l of the mobile phase solvent. This solution was subjected to high performance liquid chromatography [HPLC, Jasco UV-975, Japan, an Inertsil C8-3 column (particle size 5 μm, length and diameter, 150 × 4.6 mm)], and the mobile phase was acetonitrile adjusted to pH 5.0. The concentration of docetaxel in the blood was quantified using a mixed solution of acetic acid (49:51), a flow rate of 1 ml / min, and a UV absorbance value of 232 nm.
As a control, a conventional injection product, Taxotere® (Taxotere®) (40 mg / ml) was also orally administered to 5 Sprague-Dawley male rats (
When rectal administration of the docetaxel-containing temperature sensitive liquid suppository composition (Example 1) for rectal administration of the present invention which increased the solubility of docetaxel as an active ingredient, as shown in Table 7, the AUC was high and the absolute bioavailability compared to intravenous injection was about 30%. Came out closer. However, the docetaxel solution was orally administered at 30 mg /
The graph of blood concentrations after rectal administration of Example 1 and intravenous administration of oral administration of docetaxel solution is shown in FIG. 3.
The docetaxel-containing thermosensitive liquid suppository composition for rectal administration according to the present invention has reached an absolute bioavailability of about 30% and shows an increase in absolute bioavailability of about 10 times as compared to oral administration of docetaxel solution to a practical formulation. Not only can it be applied, but the risk of administration is much lower than that of the only existing drug, which is expected to increase the preference of medical staff or patients. It is expected to make a significant contribution to medical staff. On the other hand, it is expected to be more economically available due to the easy manufacturing method.
Claims (2)
Docetaxel-containing thermosensitive liquid suppository composition for rectal administration, characterized in that the gelation temperature is 30 ~ 36 ℃.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020100034417A KR101003890B1 (en) | 2010-04-14 | 2010-04-14 | Composition of docetaxel-loaded thermosensitive liquid suppository for rectal administration |
| PCT/KR2011/002662 WO2011129627A2 (en) | 2010-04-14 | 2011-04-14 | Docetaxel-loaded thermosensitive liquid suppository composition for rectal administration |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020100034417A KR101003890B1 (en) | 2010-04-14 | 2010-04-14 | Composition of docetaxel-loaded thermosensitive liquid suppository for rectal administration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR101003890B1 true KR101003890B1 (en) | 2010-12-30 |
Family
ID=43513369
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020100034417A KR101003890B1 (en) | 2010-04-14 | 2010-04-14 | Composition of docetaxel-loaded thermosensitive liquid suppository for rectal administration |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR101003890B1 (en) |
| WO (1) | WO2011129627A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20200123025A (en) * | 2019-04-19 | 2020-10-28 | 한양대학교 산학협력단 | Thermosensitive composition comprising phosphatidic acid and the use thereof |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101646181B1 (en) | 2015-08-18 | 2016-08-05 | 한양대학교 에리카산학협력단 | Composition of irinotecan-loaded dual-reverse thermosensitive hydrogel |
| IL300888A (en) * | 2020-08-27 | 2023-04-01 | Univ Queensland | Sol-gel composition |
| CN114712316B (en) * | 2020-12-18 | 2023-10-20 | 江苏恒瑞医药股份有限公司 | Indissolvable pharmaceutical composition and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080220074A1 (en) * | 2002-10-04 | 2008-09-11 | Elan Corporation Plc | Gamma radiation sterilized nanoparticulate docetaxel compositions and methods of making same |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997034580A1 (en) * | 1996-03-21 | 1997-09-25 | Dong Wha Pharmaceutical Industrial Co., Ltd. | Suppository composition of the drug which has gastro-intestinal disturbances or undergoes the decomposition by gastric acid |
| KR20020071407A (en) * | 2001-03-06 | 2002-09-12 | 최한곤 | Novel composite of liquid suppository for rectal administration |
| KR100446960B1 (en) * | 2001-12-04 | 2004-09-01 | 김종국 | Composition of thermosensitive emulsion for external use of prostaglandin E1 |
| KR20040028336A (en) * | 2002-09-30 | 2004-04-03 | 김종국 | Novel composite of thermosensitive antifungal gel for vaginal administration |
-
2010
- 2010-04-14 KR KR1020100034417A patent/KR101003890B1/en not_active IP Right Cessation
-
2011
- 2011-04-14 WO PCT/KR2011/002662 patent/WO2011129627A2/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080220074A1 (en) * | 2002-10-04 | 2008-09-11 | Elan Corporation Plc | Gamma radiation sterilized nanoparticulate docetaxel compositions and methods of making same |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20200123025A (en) * | 2019-04-19 | 2020-10-28 | 한양대학교 산학협력단 | Thermosensitive composition comprising phosphatidic acid and the use thereof |
| KR102357795B1 (en) * | 2019-04-19 | 2022-02-04 | 한양대학교 산학협력단 | Thermosensitive composition comprising phosphatidic acid and the use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011129627A2 (en) | 2011-10-20 |
| WO2011129627A3 (en) | 2012-02-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Nkanga et al. | Clinically established biodegradable long acting injectables: an industry perspective | |
| CA2595617C (en) | Formulations for injection of catecholic butanes, including ndga compounds, into animals | |
| JP6117939B2 (en) | Diclofenac composition | |
| EP2925293A1 (en) | Tetracycline topical formulations, preparation and uses thereof | |
| EP3505161B1 (en) | Sublingual pharmaceutical composition of edaravone and (+)-2-borneol | |
| KR101003890B1 (en) | Composition of docetaxel-loaded thermosensitive liquid suppository for rectal administration | |
| CN105748408A (en) | Micro-emulsion and micro-emulsion preparation, and preparation methods thereof | |
| CN108578356B (en) | Artemether oral microemulsion in-situ gel and preparation method thereof | |
| WO2012146057A1 (en) | Curcuminoid injection solution and intravenous injection | |
| CN107198677B (en) | Progesterone suspension type long-acting injection, preparation method thereof and progesterone suspension injection powder | |
| US9913814B2 (en) | Tamper resistant immediate release capsule formulation comprising tapentadol | |
| JP2023075278A (en) | Pharmaceutical bio-dissolvable gels for drug delivery | |
| CN101088499B (en) | Dry asarol emulsion and its prepn and application | |
| US20130137769A1 (en) | Injectable Preparations Of Diclofenac And Its Pharmaceutically Acceptable Salts | |
| US20220370359A1 (en) | Fulvestrant pharmaceutical composition, preparation method therefor, and application thereof | |
| CN102266298A (en) | Pharmaceutical composition of pemetrexed disodium | |
| JP2021536485A (en) | Injectable sustained release antibiotic formulation | |
| CN101057845B (en) | Bulleyaconitin A dry emulsion and its preparation method and application | |
| CN111481559B (en) | High-concentration fulvestrant composition and preparation method thereof | |
| US20240108603A1 (en) | Material and method for treating cancer | |
| KR101010411B1 (en) | Pharmaceutical preparation composition of ondansetron liquid suppository for rectal delivery | |
| JP2004131472A (en) | Ointment for treatment of hemorrhoid | |
| KR100679925B1 (en) | Novel composite of rectal suppository containing 5-fluorouracil | |
| Al-Wiswasi et al. | Formulation and in vitro evaluation of in-situ gelling liquid suppositories for naproxen | |
| WO2022269572A1 (en) | Pharmaceutical compositions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| A302 | Request for accelerated examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20131014 Year of fee payment: 4 |
|
| FPAY | Annual fee payment |
Payment date: 20141014 Year of fee payment: 5 |
|
| FPAY | Annual fee payment |
Payment date: 20151109 Year of fee payment: 6 |
|
| FPAY | Annual fee payment |
Payment date: 20161219 Year of fee payment: 7 |
|
| LAPS | Lapse due to unpaid annual fee |