CN1518984A - Preparation of non-intestinal tract administration Adefovir and Adefovir Dipivixi - Google Patents
Preparation of non-intestinal tract administration Adefovir and Adefovir Dipivixi Download PDFInfo
- Publication number
- CN1518984A CN1518984A CNA031149847A CN03114984A CN1518984A CN 1518984 A CN1518984 A CN 1518984A CN A031149847 A CNA031149847 A CN A031149847A CN 03114984 A CN03114984 A CN 03114984A CN 1518984 A CN1518984 A CN 1518984A
- Authority
- CN
- China
- Prior art keywords
- adefovirdipivoxil
- salt
- acid
- drug delivery
- sodium
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A medicine in the form of powder or liquid injection for treating acute hepatitis B is prepared from adefovirdipivoxil or adefovirdipivoxil-dipivalyoxy methylester or physiologically receptable their salts, water-soluble filler, and pH regulator. Its advantages are easy absorption and high biological utilization rate.
Description
Technical field
The present invention relates to the improvement of pharmaceutical dosage form, more specifically refer to the non-intestinal drug delivery agent of the two pivaloyl oxygen base methyl ester of medicine adefovirdipivoxil and adefovirdipivoxil.
Background technology
Adefovirdipivoxil (Adefovir, structural formula See Figure levoform), chemical name: 9-[2-(phosphinyl methoxyl group) ethyl] adenine.The two pivaloyl oxygen base methyl ester of adefovirdipivoxil (Adefovir Dipivoxil, the right formula of structural formula See Figure), i.e. two pivaloyl oxygen base methyl ester of adefovirdipivoxil, chemical name: 9-[2-two (pivaloyloxymethoxy) phosphinyl]-methoxyl group] ethyl] adenine.
The two pivaloyl oxygen base methyl ester of adefovirdipivoxil adefovirdipivoxil
The two pivaloyl oxygen base methyl ester of adefovirdipivoxil belong to the adenylic acid analog, be converted into activated product through hydrolysis in vivo---adefovirdipivoxil, it and natural substrate deoxyadenine triphosphoric acid are competed hepatitis b virus dna polymerase, after entering the viral DNA chain, cause the synthetic termination of its DNA chain, thereby hinder virus replication.And it is strong to viral DNA synzyme selectivity.Has the broad-spectrum disease resistance cytotoxic activity.
The two pivaloyl oxygen base methyl ester of the adefovirdipivoxil of listing are oral administration at present, and preparation is tablet or capsule.Satisfy the convenience of long-term prescription.But its human bioavailability is 40%-60% only, and simultaneously for the viral hepatitis acute attack stage, patient often has symptoms such as nausea and vomiting, is unfavorable for oral administration, to reach effective blood drug level rapidly.Need parenterai administration this moment, i.e. intramuscular injection, intravenous injection or instillation give effective dose, so that suppress duplicating of hepatitis virus, relief of symptoms rapidly.So the injection preparation of the two pivaloyl oxygen base methyl ester of preparation adefovirdipivoxil is necessary.
Adefovirdipivoxil is the active metabolite of the two pivaloyl oxygen base methyl ester of adefovirdipivoxil, and any preparation listing is not arranged as yet.Cause is difficult to by intestinal absorption, and oral administration biaavailability is very low, does not reach the effective blood drug concentration that suppresses virus replication.
Summary of the invention
The object of the invention is because the two pivaloyl oxygen base methyl ester of adefovirdipivoxil and adefovirdipivoxil deficiency such as absorption difference in intestinal, thus their non-intestinal drug delivery agents are provided, with the bioavailability that improves them and the characteristics of instant effect, the treatment of suitable acute attack stage.
Two pivaloyl oxygen base methyl ester of the adefovirdipivoxil of so-called injection and adefovirdipivoxil are according to " the definition among two appendix IB of Chinese pharmacopoeia version in 2000, refer to be sealed in the sterile solid in the container, this container can be a glass ampule, more suitably be that vial adds plug and adds aluminium lid sealing again, add suitable solvent for injection dissolving back during use for parenterai administration, i.e. the preparation of muscle, subcutaneous, vein or intra-arterial injection.
The two pivaloyl oxygen base methyl ester of adefovirdipivoxil are water insoluble, find after deliberation, and the two pivaloyl oxygen base methyl ester of 200mg adefovirdipivoxil can be dissolved in the 40ml pH value less than in 4.0 the acidic aqueous solution; But the two pivaloyl oxygen base methyl ester of adefovirdipivoxil are unstable medium-term and long-term placement of this solution, place degraded in 24 hours under the room temperature and surpass 5%.So be not suitable for making injection, the present invention adopts freeze drying process to make sterile injection powder; Also can adopt micronization under the aseptic condition, specifically be exactly comminution by gas stream or claim method of micronization such as fluid energy mill, vibrations mill, ball milling, be processed into behind the powder aseptic subpackagedly, make sterile injection powder.Above-mentioned sterile injection powder is injected or is instiled facing with suitable dissolution with solvents dilution posterior veins such as before adding injection water, normal saline or 5% glucose solution.Adefovirdipivoxil also can adopt normal freeze-drying technology or sterilized powder packing prepared to become the adefovirdipivoxil of injection.
When freeze-drying prepares the sterile injection powder of two pivaloyl oxygen base methyl ester of adefovirdipivoxil and adefovirdipivoxil, must add water miscible filler and pH regulator agent.When freeze-drying prepares the sterile injection powder of adefovirdipivoxil, can add water miscible filler and pH regulator agent, also can not add any adjuvant, only with water dissolution, moisture is removed in lyophilization then, becomes bulk or the powder of Yi Rong; Because adefovirdipivoxil is soluble in water.
Water-soluble filler can be one of following compositions or two or three: mannitol, sorbitol, lactose, maltose, gelatin, polyvidone, dextran, glucose, citric acid, potassium chloride, sodium chloride, sodium hydrogen phosphate, sodium carbonate etc.The water-soluble filler consumption is that every bottle of 5mg is to 500mg.Comparatively suitable consumption is that 50mg is to 200mg.Only consumption is about 100mg.By weight percentage, above-mentioned water-soluble filler accounts for the 50%-99.9% of prescription total amount, comparatively suitable ratio 70%-99%, and the best is 90%-99%.
Here the pharmaceutic adjuvant that is suitable for regulator solution pH can be nonvolatile acid such as citric acid, malic acid, phosphoric acid, sulphuric acid, sulfurous acid, and sodium hydroxide or potassium or ammonium, sodium carbonate or potassium or ammonium salt, sodium bicarbonate or potassium or ammonium salt, sodium phosphate or potassium or ammonium salt, disodium-hydrogen or potassium or ammonium salt, sodium dihydrogen phosphate or potassium or acceptable organic or inorganic bronsted lowry acids and bases bronsted lowry of physiology and salt such as ammonium salt, citric acid trisodium salt, sodium acetate or ammonium salt.The consumption of pH regulator agent requires required amount with the pH that regulates solution before the lyophilizing to regulation.
When sterilized powder packing legal system is equipped with two pivaloyl oxygen base methyl ester of injection adefovirdipivoxil or adefovirdipivoxil, also need above-mentioned water-soluble filler and pH regulator agent.Can pulverize together, also can mix behind the pulverize separately.
The specification of the two pivaloyl oxygen base methyl ester of injection adefovirdipivoxil also changes according to its dosage of difference of purposes, be generally every unit preparation (per ampoule or every bottle) and contain the two pivaloyl oxygen base methyl ester 1mg-20mg of adefovirdipivoxil, more suitably specification can be every bottle and contains the two pivaloyl oxygen base methyl ester 5mg-10mg of adefovirdipivoxil, and optimum is 6mg.Be used for the treatment of viral hepatitis, the dosage of clinical use is for once a day, each 1mg-20mg, and more suitable is 5mg-10mg, optimum is 6mg.By weight percentage, the two pivaloyl oxygen base methyl ester of adefovirdipivoxil account for the 0.1%-50% of prescription total amount (disregarding solvent), comparatively suitable ratio 1%-30%, and the best is 1%-10%.
The specification of injection adefovirdipivoxil is every bottle and contains adefovirdipivoxil 0.5mg-11mg, and more suitably specification can be every bottle and contains adefovirdipivoxil 2.7mg-5.45mg, and optimum is 3.3mg.Be used for the treatment of viral hepatitis, the dosage of clinical use is for once a day, each 0.5mg-11mg, and more suitable is 2.7mg-5.45mg, optimum is 3.3mg.By weight percentage, adefovirdipivoxil accounts for the 0.1%-50% of prescription total amount (disregarding solvent), comparatively suitable ratio 0.5%-30%, and the best is 1%-10%.
Be fit to make the two pivaloyl oxygen base methyl ester of injection adefovirdipivoxil and can be its above free type, also can be the physiologically acceptable salt of the two pivaloyl oxygen base methyl ester of adefovirdipivoxil, for example Hemisulphate, hydrobromate, hydrochlorate, nitrate, mesylate, esilate, beta-naphthalenesulfonic-acid salt, (S)-camsilate, succinate, maleate, Ascorbate, nicotinate, pantothenic acid, glycyrrhizic acid and enoxolone.Its unit preparation specification and clinical dosage are pressed molecular weight, according to the amount conversion of the two pivaloyl oxygen base methyl ester of above-mentioned free type adefovirdipivoxil.
Be fit to make the injection adefovirdipivoxil and can be its above free type, also can be the physiologically acceptable salt of adefovirdipivoxil, for example Hemisulphate, hydrobromate, hydrochlorate, nitrate, mesylate, esilate, beta-naphthalenesulfonic-acid salt, (S)-camsilate, succinate, maleate, Ascorbate, nicotinate, pantothenic acid, glycyrrhizic acid and enoxolone.Its unit preparation specification and clinical dosage are pressed molecular weight, according to the amount conversion of above-mentioned free type adefovirdipivoxil.
Being fit to make the injection adefovirdipivoxil can also be monopotassium salt, di-potassium, single sodium salt, disodium salt, mono-ammonium, di-ammonium salts, single methylamine salt, dimethylamine salt, mono aminoethane salt, diethyl amine salt, monoethanolamine salt, diethanolamine salt, single Radix Sophorae Flavescentis alkali salt and the two Radix Sophorae Flavescentis alkali salts of adefovirdipivoxil.Its unit preparation specification and clinical dosage are pressed molecular weight, according to the amount conversion of above-mentioned free type adefovirdipivoxil.
Discover that adefovirdipivoxil is dissolvable in water water, 500ml water dissolvable 1g adefovirdipivoxil under the room temperature, pH value is 3.5; Find that also the dissolubility of adefovirdipivoxil in water is relevant with pH, must raise that its dissolubility also increases with pH value, when pH is 7.5,5ml water dissolvable 0.1g adefovirdipivoxil.Adefovirdipivoxil not only has suitable dissolubility, and also has excellent storage stability.In the scope of pH3-9, its solution room temperature is stored to few 2 years and stablizes.Therefore adefovirdipivoxil can directly be mixed with the aqueous solution of sterilization, be sub-packed in glass ampule (0.5ml, 1ml, 1.5ml, 2ml, 5ml, 10ml, 20ml), vial (5ml, 10ml, 20ml), infusion bottle or transfusion plastic bag (50ml, 100ml, 200ml, 250ml, 500ml), be prepared into aseptic apyrogenic injection, for intramuscular injection (2ml and following unit preparation), direct intravenous injection (50ml and following unit preparation), intravenous drip (50ml is to the unit preparation of 500ml), or injection normal saline, glucose for injection solution dilution posterior vein instillation (the unit preparation of 0.5ml-50ml).
The manufacturing of above-mentioned adefovirdipivoxil injection adopts conventional injection manufacturing process to carry out.
Solvent is for meeting " the water for injection of two regulations of Chinese pharmacopoeia version in 2000.Become solution with this water for injection dissolving adefovirdipivoxil, the pH value of solution is between 3-9, and more suitably pH value is between 3.5-8, and best pH scope is the arbitrary value between the 4-7.It also is the acceptable pH value of Human Physiology.Being used to regulate pH value reagent is pH regulator agent and the phase application quantity that preamble has been mentioned.Adefovirdipivoxil injection for direct intravenous injection and instillation also requires to have equal and slightly high osmotic pressure in blood of human body, can add sodium chloride (usual amounts is 0.9%w/v), glucose (usual amounts is 5%w/v) isosmoticity regulator, make the adefovirdipivoxil injection meet above-mentioned requirements.
The specification of adefovirdipivoxil injection is that every unit preparation (each ampoule or every bottle or every bag) contains adefovirdipivoxil 0.5mg-11mg, and more suitably specification can be that every unit preparation contains adefovirdipivoxil 2.7mg-5.45mg, and optimum is 3.3mg.Be used for the treatment of viral hepatitis, the dosage of clinical use is for once a day, each 0.5mg-11mg, and more suitable is 2.7mg-5.45mg, optimum is 3.3mg.
Making the adefovirdipivoxil injection can be the free type of the above indication of adefovirdipivoxil, also can be the physiologically acceptable salt of adefovirdipivoxil, for example Hemisulphate, hydrobromate, hydrochlorate, nitrate, mesylate, esilate, beta-naphthalenesulfonic-acid salt, (S)-camsilate, succinate, maleate, Ascorbate, nicotinate, pantothenic acid, glycyrrhizic acid and enoxolone.Can also be monopotassium salt, di-potassium, single sodium salt, disodium salt, mono-ammonium, di-ammonium salts, single methylamine salt, dimethylamine salt, mono aminoethane salt, diethyl amine salt, monoethanolamine salt, diethanolamine salt, single Radix Sophorae Flavescentis alkali salt and the two Radix Sophorae Flavescentis alkali salts of adefovirdipivoxil.Its unit preparation specification and clinical dosage are pressed molecular weight, according to the amount conversion of above-mentioned free type adefovirdipivoxil.
The specific embodiment
Following examples are to further annotation of the present invention, but not limitation of the present invention.
Embodiment 1 freeze-drying prepares the two pivaloyl oxygen base methyl ester of injection adefovirdipivoxil
Prescription:
The two pivaloyl oxygen base methyl ester 6.0g of adefovirdipivoxil
Citric acid one water thing 5.5g
Mannitol 100g
Water for injection adds to 1000ml
Make 1000 bottles altogether
Preparation technology
Get the citric acid of recipe quantity, be dissolved in an amount of water for injection, the two pivaloyl oxygen base methyl ester of the adefovirdipivoxil of recipe quantity are added, stir and make dissolving, add the about 900ml of injection water, add the mannitol of recipe quantity again, stir and make dissolving; Sodium hydroxide solution with 0.1mol/L is regulated about pH3.5, adds to the full amount of water for injection, and adds 0.03% (m/v) needle-use activated carbon and stirs 30 minutes, through 0.22 μ m microporous filter membrane malleation aseptic filtration; After the inspection of semifinished product is qualified, in the aseptic subpackaged vial behind washing and sterilizing, every bottled amount 1ml; Through frozen drying about 24 hours, seal promptly.The qualified back of product inspection packing.
Embodiment 2 freeze-dryings prepare the injection adefovirdipivoxil
Prescription:
Adefovirdipivoxil 3.3g
Citric acid trisodium 5.5g
Mannitol 100g
Water for injection adds to 1000ml
Make 1000 bottles altogether
Preparation technology
Get the sodium citrate of recipe quantity, be dissolved in an amount of water for injection,, stir and make dissolving, add the about 900ml of injection water, add the mannitol of recipe quantity again, stir and make dissolving the adefovirdipivoxil adding of recipe quantity; Citric acid soln with 0.1mol/L is regulated about pH5.5, adds to the full amount of water for injection, and adds 0.03% (m/v) needle-use activated carbon and stirs 30 minutes, through 0.22 μ m microporous filter membrane malleation aseptic filtration; After the inspection of semifinished product is qualified, in the aseptic subpackaged vial behind washing and sterilizing, every bottled amount 1ml; Through frozen drying about 24 hours, seal promptly.The qualified back of product inspection packing.
Embodiment 3 adefovirdipivoxil injection are for intramuscular injection.
Prescription:
Adefovirdipivoxil 3.3g
Water for injection adds to 1000ml
Make 1000 bottles altogether
Preparation technology:
Take by weighing the adefovirdipivoxil of recipe quantity, add injection water 900ml, be heated to 80 ℃ and make dissolving, regulate pH to 3.5-4.5 with 0.1mol/1NaOH, add to the full amount of water for injection, add active carbon, measure intermediate amounts, qualified after, earlier by the sand rod, again through 0.45 μ filtering with microporous membrane, the filtrate fill is in the 2ml ampoule bottle, and every bottled amount 1ml seals, 100 ℃ of circulation steam sterilizations 30 minutes, lamp inspection, lettering, packing are promptly.
Embodiment 4 adefovirdipivoxil injection, injection for intravenous.
Prescription:
Adefovirdipivoxil 3.3g
Sodium chloride 9.0g
Water for injection is an amount of
Full dose 1000ml
Preparation technology:
Take by weighing adefovirdipivoxil, the sodium chloride of recipe quantity, add injection water 900ml, be heated to 80 ℃ of dissolvings, reuse 0.1mol/lNaOH regulates pH to 4.0-5.0, adds to the full amount of water for injection, and adds active carbon 0.01%w/v, stir 15min, by the decarburization of sand rod, again through 0.45 μ filtering with microporous membrane, the filtrate fill is in the 100ml glass infusion bottle, put mylar, cover plug, gland, 115 ℃ of circulation steam sterilizations 30 minutes, lamp inspection, packing are promptly.
Claims (11)
1, two pivaloyl oxygen base methyl ester of a kind of adefovirdipivoxil and its physiologically acceptable salt or adefovirdipivoxil and its physiologically acceptable salt non-intestinal drug delivery agent by adefovirdipivoxil and its physiologically acceptable salt, water-soluble filler, pH regulator joint agent, water for injection, osmotic pressure regulator is formulated or the two pivaloyl oxygen base methyl ester of adefovirdipivoxil and their acceptable salt, water-soluble filler, pH regulator agent are formulated.
2,, it is characterized in that the prescription (percentage by weight) of the two pivaloyl oxygen base methyl ester injectable powder of adefovirdipivoxil is according to the described non-intestinal drug delivery agent of claim 1:
The two pivaloyl oxygen base methyl ester 0.1%-50% of adefovirdipivoxil
Water-soluble filler 50%-99.9%
The pH regulator agent is an amount of
3,, it is characterized in that adefovirdipivoxil injectable powder prescription (percentage by weight) is according to the described non-intestinal drug delivery agent of claim 1:
Adefovirdipivoxil or adefovirdipivoxil physiologically acceptable salt 0.1%-50%
Water-soluble filler 50%--99.9%
The pH regulator agent is an amount of
4, according to the described non-intestinal drug delivery agent of claim 1, the pH value that it is characterized in that the adefovirdipivoxil injection is between 3 to 9, and optimal pH is between 4 to 7.
5, according to the described non-intestinal drug delivery agent of claim 1, it is characterized in that described water-soluble filler be one of following ingredients or two or three;
Mannitol, sorbitol, lactose, maltose, gelatin, polyvidone, dextran, glucose, citric acid, potassium chloride, sodium chloride, sodium hydrogen phosphate, sodium carbonate.
6,, it is characterized in that described pH regulator agent is according to the described non-intestinal drug delivery agent of claim 1:
Nonvolatile acid such as citric acid, malic acid, phosphoric acid, sulphuric acid, sulfurous acid, and sodium hydroxide or potassium or ammonium, sodium carbonate or potassium or ammonium salt, sodium bicarbonate or potassium or ammonium salt, sodium phosphate or potassium or ammonium salt, disodium-hydrogen or potassium or ammonium salt, sodium dihydrogen phosphate or potassium or acceptable organic or inorganic bronsted lowry acids and bases bronsted lowry of physiology and salt such as ammonium salt, citric acid trisodium salt, sodium acetate or ammonium salt.
7, according to the described non-intestinal drug delivery agent of claim 2, what it is characterized in that the middle adefovir dipivoxil of adefovir dipivoxil injectable powder prescription (percentage by weight) is 1%-30% than proper ratio, and optimal proportion is 1%-10%.
8, according to the described non-intestinal drug delivery agent of claim 2, it is characterized in that preparing when using in the viral hepatitis medicine, the consumption of the two every unit of pivaloyl oxygen base methyl ester of adefovirdipivoxil (per ampoule or every bottle) is 1mg-20mg, and more suitably consumption is 5mg-10mg, and optimum amount is 6mg.
9, according to the described non-intestinal drug delivery agent of claim 3, when it is characterized in that in preparation viral hepatitis medicinal application, the every unit of adefovirdipivoxil (per ampoule or every bottle) consumption is 0.5mg-11mg, and more suitably consumption is 2.7mg-5,45mg, optimum consumption are 3.3mg.
10,, it is characterized in that the physiologically acceptable salt of the two pivaloyl oxygen base methyl ester of adefovirdipivoxil is Hemisulphate, hydrobromate, hydrochlorate, nitrate, mesylate, esilate, beta-naphthalenesulfonic-acid salt, (S)-camsilate, succinate, maleate, Ascorbate, nicotinate, pantothenic acid, glycyrrhizic acid and enoxolone according to the described non-intestinal drug delivery agent of claim 1.
11, according to the described non-intestinal drug delivery agent of claim 1, the physiologically acceptable salt that it is characterized in that adefovirdipivoxil is a Hemisulphate, hydrobromate, hydrochlorate, nitrate, mesylate, esilate, beta-naphthalenesulfonic-acid salt, (S)-camsilate, succinate, maleate, Ascorbate, nicotinate, pantothenic acid, glycyrrhizic acid, enoxolone, monopotassium salt, di-potassium, single sodium salt, disodium salt, mono-ammonium, di-ammonium salts, single methylamine salt, dimethylamine salt, mono aminoethane salt, the diethyl amine salt, monoethanolamine salt, diethanolamine salt, single Radix Sophorae Flavescentis alkali salt and two Radix Sophorae Flavescentis alkali salts.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031149847A CN1518984A (en) | 2003-01-20 | 2003-01-20 | Preparation of non-intestinal tract administration Adefovir and Adefovir Dipivixi |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031149847A CN1518984A (en) | 2003-01-20 | 2003-01-20 | Preparation of non-intestinal tract administration Adefovir and Adefovir Dipivixi |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1518984A true CN1518984A (en) | 2004-08-11 |
Family
ID=34284051
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031149847A Pending CN1518984A (en) | 2003-01-20 | 2003-01-20 | Preparation of non-intestinal tract administration Adefovir and Adefovir Dipivixi |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1518984A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100384427C (en) * | 2003-12-05 | 2008-04-30 | 天津药物研究院 | Injection preparation containing active component adefuwei or its salt and its preparation method |
| CN1799550B (en) * | 2005-01-04 | 2010-12-29 | 沈阳药科大学 | Highly efficient formulation of hepsera and preparation method thereof |
-
2003
- 2003-01-20 CN CNA031149847A patent/CN1518984A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100384427C (en) * | 2003-12-05 | 2008-04-30 | 天津药物研究院 | Injection preparation containing active component adefuwei or its salt and its preparation method |
| CN1799550B (en) * | 2005-01-04 | 2010-12-29 | 沈阳药科大学 | Highly efficient formulation of hepsera and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1138541C (en) | Pharmaceutically stable oxaliplatinum prepn. | |
| CN102670497A (en) | Stable S-oxiracetam preparation for injection and preparation method of same | |
| CN100451023C (en) | Levo-ornidazole phosphate, preparing process and use thereof | |
| CN102114271A (en) | Multi-medicament loaded calcium phosphate cement powder | |
| CN100389772C (en) | Use of zolendronate for mfg. medicament for treatment of bone metabolism diseases | |
| US11147926B2 (en) | Intrathecal baclofen pharmaceutical dosage forms and related delivery system | |
| KR20050084829A (en) | Administration form for pharmaceutically active peptides with sustained release and method for the production thereof | |
| CN107126432A (en) | Lian Bizhi Neulized inhalation pharmaceutical solutionses and preparation method thereof | |
| CN1803811A (en) | Nitro imidazole derivative, its preparation method and uses | |
| CN1729988A (en) | Composite medicine of creatine phosphate sodium and magnesium salt | |
| CN1518984A (en) | Preparation of non-intestinal tract administration Adefovir and Adefovir Dipivixi | |
| CN1679924A (en) | Compound insulin energy mistura preparation and use thereof | |
| CN1351866A (en) | Levo-potassium magnesium aspartate freeze drying powder injection and preparing method | |
| CN101829135A (en) | Injection preparation with citicoline sodium and inosine as active ingredients, and application thereof | |
| CN104706655A (en) | Meglumine adenosine cyclophosphate powder injection medicine composition for injection and preparation method thereof | |
| CN1437942A (en) | Vinorebin powder injection and preparation method | |
| CN1565465A (en) | Injection preparation containing breviscapine active component and its preparation method | |
| CN1251681C (en) | Highly concentration water-soluble vitamin for intravenous injection and preparation and use | |
| CN101780084A (en) | Injection composition using levo leucovorin or salt thereof as major ingredients | |
| CN101019872B (en) | Nanometer antiviral liposome medicine and its preparation | |
| CN105708793A (en) | Aconitine injection for intrathecal injection and preparation method thereof | |
| CN1511037A (en) | Nonintestinal estramustine phosphate and albumin preparations | |
| CN101190937B (en) | Compound with liver-protecting activity | |
| CN104906587B (en) | A kind of Foscarnet sodium vitreum intracavitary slow releasing pharmaceutical | |
| CN1177583C (en) | For mulations for parenteral use of estramustine phosphate with improved pharmacological properties |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |