US20130338064A1 - Insulin-lipid complex,preparation method therefor, and preparation thereof - Google Patents
Insulin-lipid complex,preparation method therefor, and preparation thereof Download PDFInfo
- Publication number
- US20130338064A1 US20130338064A1 US13/810,098 US201113810098A US2013338064A1 US 20130338064 A1 US20130338064 A1 US 20130338064A1 US 201113810098 A US201113810098 A US 201113810098A US 2013338064 A1 US2013338064 A1 US 2013338064A1
- Authority
- US
- United States
- Prior art keywords
- insulin
- lipid
- solution
- complex
- solvent
- 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.)
- Abandoned
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
- C07K17/02—Peptides being immobilised on, or in, an organic carrier
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the invention relates to an insulin-lipid complex and a method for the preparation thereof.
- the invention also relates to an oil solution containing the insulin-lipid complex, the use thereof in the preparation of formulations for sustained-released injection and non injection administration, and the use of novel vesicles (liposomes) that contain the insulin-lipid complex in the preparation of a formulation for non-injection administration.
- the invention generally relates to the field of medicine.
- Phospholipid complexes were discovered by the Italian scholar, Bombardelli, in the study of liposomes. Early research on phospholipid complexes was mostly on flavonoid containing phenolic hydroxyls or polyphenols. Subsequently, further research proved that in addition to phenolic hydroxyls, some polar groups such as alcoholic hydroxyl groups, amide groups, or carbonyl groups might react with the hydrophilic head of phospholipids or other lipid materials (such as cholesterol, sodium cholate, etc.) to form a complex spheroid by intermolecular hydrogen bonding or VDW (Van der Waals' force). Both hydrophilic drugs and lipophilic drugs can form lipid complex as long as they contain a polar group for forming the complex. Formation of a lipid complex can significantly improve the lipophilicity and oil solubility of drugs.
- vesicles also known as liposomes
- a liposome is an artificially-prepared vesicle composed of a lipid bilayer with the hydrophilic heads of the phospholipid molecules facing outward and the hydrophobic tails facing inward.
- a phospholipid complex is a lipophilicity spheroid, fixed by the interactions between the polar groups of active ingredients and the hydrophilic heads of phospholipids. The hydrophilic heads are encapsulated, whereas the hydrophobic tails do not participate in the recombination reaction and can move freely.
- a liposome vesicle may be formed by hundreds or thousands of phospholipid molecules, with the hydrophilic heads of phospholipids constituting the outer and inner layers of the lipid bilayer, and with the hydrophobic tails in the middle interlayer.
- Lipophilic drugs can be encapsulated in the interlayer of a bilayer membrane (blue square in the figure), with high and stable entrapment efficiency, and are not prone to leakage.
- hydrophilic drugs can only be kept in the interior of the vesicles or around the exterior periphery of the vesicles and mostly around the exterior periphery of the vesicles due to the difficulty in getting the drugs enter the vesicles, which is associated with poor stability and are prone to leakage. Liposomes of lipophilic drugs are significantly better than liposomes of hydrophilic drugs in terms of membrane permeability.
- lipid complex can be prepared first to improve lipophilicity, and then liposome vesicles can be prepared; this can improve entrapment efficiency and stability, and improve membrane permeability.
- Insulin is susceptible to gastric acid and various proteolytic enzymes in the digestive tract and because of its big molecular weight, has difficulty penetrating the gastrointestinal barrier, normal oral preparations are ineffective, and subcutaneous injection is still the main route of administration, but long-term frequent injection in patients has poor compliance.
- the insulin is lacking in lipophilicity, limiting the preparation and development of the microparticle support.
- Insulin liposomes are the most reported particulate carriers both at home and abroad, but with big molecular weight and strong hydrophilicity, most drugs exist in the periphery of the phospholipid bilayer, entrapment efficiency is low, are prone to leakage, and improvement of the stability of insulin in the gastrointestinal tract and mucosal permeability are limited.
- the preparation of nanoparticles and microspheres is mostly in organic solvent systems, and insulin has poor solubility in organic solvents, low entrapment efficiency, is only adsorbed on the particle surface, is prone to release after drug administration, and the stabilization effect is likewise poor.
- the insulin molecule contains a large number of polar groups, such as acylaminos, phenolic hydroxyls, hydroxys, and carbonyls, all groups have the ability to generate intermolecular interactions with hydrophilic ends of lipid materials and form lipid complexes, thereby improving the lipophilicity, and breaking through the limits of microparticle carrier preparations.
- polar groups such as acylaminos, phenolic hydroxyls, hydroxys, and carbonyls
- Insulin is a protein consisting of two subunit polypeptides commonly referred to as the A-chain and the B-chain, and its molecular weight is close to 6000.
- the human Insulin (Insulin Human) A-chain has 21 amino acids of 11 kinds, and the B-chain has 30 amino acids of 15 kinds, for a total of 51 amino acids of 26 kinds. Insulin is insoluble in water and organic solvents, but soluble in acid diluted methanol, pH 7.4 phosphate buffer, low-concentration acid and low-concentration alkali.
- Insulin contains a lot of polar groups and molecular interactions may occur between the hydrophilic ends of lipid materials, and meets the requirement to form lipid complexes. But the structural features and physical and chemical properties of insulin proteins make the preparation of lipid complexes extremely difficult, and the biggest obstacle is the choice of complex solvents.
- insulin contains 53 acylamino groups, 4 phenolic hydroxyl groups, 12 alcoholic hydroxyl groups, and these groups are able to combine with phospholipids, and 1 mole of the drug needs about 70 moles of phospholipids in theory (the weight ratio is about 1:10).
- the feed volume of lipid material should be slightly higher than the theoretical value, at the 1.5 times of theoretical value, and the maximum amount of lipid material shall not exceed 15 times of drug mass that is, it is economical and reasonable that the phospholipid dosage should be controlled to ⁇ 15 times the insulin mass.
- patent No. 01140047 when the mass of the phospholipid was as high as 150 times the insulin, it still cannot be fully compounded, which indicates that the compounding efficiency is too low with water as the solvent.
- the inventor performed a verification of the method of patent No. 97196069.
- the recombination rate determination method HPLC Quantitative methods
- HPLC Quantitative methods HPLC Quantitative methods
- the mixture ratio of the drug and lipid materials has not been scientifically optimized, obtains complexes with low recombination rate and the improvement of the solubility in oil phase is limited, creates oil solutions with low drug loading capacity and manifests instability phenomena such as being prone to sedimentation in storage process, etc.
- the present invention provides an insulin-lipid complex, compounded from insulin and lipid material in an organic solvent system containing a low boiling point acid, with the mass ratio of insulin and lipid material in the complex being 1:3 ⁇ 1:15; 1:4 ⁇ 1:12 being preferred; and 1:5 ⁇ 1:10 being more preferred.
- the present invention provides an insulin-lipid complex, the insulin being selected from the group consisting of natural insulin, porcine insulin, bovine insulin, recombinant human insulin and intermediate-acting and long-acting insulin, recombinant human insulin is preferred;
- the lipid material is selected from the group consisting of natural phospholipids, synthetic phospholipids, cholesterol, cholic acid, salts thereof, and a combination thereof, natural phospholipids being preferred for the lipid material, and egg yolk phospholipid, or soybean phospholipid being preferred for the natural phospholipid.
- the present invention provides an insulin-lipid complex, containing one or more ingredients selected from antioxidants, metal chelating agents and protease inhibitors.
- the present invention provides an insulin-lipid complex, organic solvents used being complex solvents containing a low boiling point acid, wherein, the low boiling point acid is selected from the group consisting of trifluoroacetic acid, hydrogen chloride, and a combination thereof, and the organic solvent being selected from the group consisting of methanol, tetrahydrofuran, DMSO, chloroform, dichloromethane, ether and a combination thereof.
- Method 1 take some organic solvent, add some trifluoroacetic acid first or some hydrogen chloride gas, then add the insulin and lipid material, stiffing fully to compound and form a transparent solution, remove the organic solvent by rotary evaporation or the spray drying method, and drying.
- Method 2 take some organic solvent, dissolve the lipid material in it, and add insulin, stiffing while adding some hydrogen chloride gas or some trifluoroacetic acid to form a transparent solution, stirring or ultrasonic processing for a given time at room temperature, fully compound the insulin and lipid material, remove the organic solvent by rotary evaporation or the spray drying method, and drying.
- Method 3 dissolve insulin in solvent A containing some trifluoroacetic acid or hydrogen chloride gas, to form a pellucid insulin solution, and dissolve lipid material in solvent B to form a pellucid lipid solution, mix the insulin solution and lipid solution even, and then perform reduced pressure distillation with a water bath, and remove the solvent by pumping, and drying.
- Method 4 dissolve insulin in solvent A containing some trifluoroacetic acid or hydrogen chloride gas to form a pellucid insulin solution, and dissolve a lipid material in solvent B to form a pellucid lipid solution, mix the insulin solution and lipid solution with reduced pressure distillation under water bathing conditions and a given temperature, and slowly add some solvent B during the distillation process, and remove the solvent by pumping, and drying.
- Said “organic solvent” in Method 1) and Method 2) is selected from the group consisting of methanol, tetrahydrofuran, DMSO, or a combination thereof, methanol being preferred.
- the added amount of trifluoroacetic acid and hydrogen chloride gas are preferably standardized on the insulin being completely dissolved thereby, the concentration of acid in the organic solvent being 0.01-0.5%, and preferably 0.05-0.1% (weight/volume, g/ml).
- Said “solvent A” in Method 3) and Method 4) is selected from a group consisting of methanol, tetrahydrofuran, DMSO or a combination thereof, methanol being preferred;
- Said “solvent B” is selected from a group consisting of chloroform, dichloromethane or a combination thereof, dichloromethane being preferred.
- concentration of TCA or hydrogen chloride gas in solvent A is about 0.01-0.5%, 0.05-0.1% being preferred.
- the dosage of solvent B is about 3-8 times of solvent A, 4-6 times being preferred.
- the concentration of insulin should be controlled to 0.5 ⁇ 30 mg/ml, 1.0 ⁇ 10.0 mg/ml being preferred.
- the “room temperature” in “stirring at room temperature or ultrasonic processing for a given time” should be controlled at 15° C.° C. ⁇ 30° C., for example 15° C., 20° C., 25° C. or 30° C.; “given time” means within 30 min, for example 30 min, 20 min, 10 min or 5 min.”
- the method for removing the organic solvent can be the rotary evaporation method, and also the freeze drying method, or another method to remove solvent and with no influence on the stability of drugs can be adopted.
- the solvent by the rotary evaporation method below 40° C., and for example, it can be 35° C. and 30° C. or 25° C.
- the present invention provides a formulation for an insulin oil solution, and it contains the insulin-lipid complex of this invention and oil.
- the oil is selected from the group consisting of LCT (Long chain Triglyceride), MCT (Medium Chain Triglyceride), Glyceryl monooleate, ethyl oleate, isopropyl myristate or a combination thereof.
- the oil solution containing the insulin-lipid complex of this invention is characterized by an emulsifier selectable from one or several of Tween 80, Span 20, Brij, Ethoxylated hydrogenated castor oil (Cremphor RH40), polyoxyethylated castor oil (Cremphor EL35) and Labrosal emulsifier being freely selected and added.
- an emulsifier selectable from one or several of Tween 80, Span 20, Brij, Ethoxylated hydrogenated castor oil (Cremphor RH40), polyoxyethylated castor oil (Cremphor EL35) and Labrosal emulsifier being freely selected and added.
- the oil solution containing an insulin-lipid complex of this invention can include one or several co-emulsifiers freely selectable from propanediol, PEG400 and Transcutol.
- the oil solution containing an insulin-lipid complex of this invention can have a drug content of 12 mg/g, 10 mg/g, 8 mg/g, 6 mg/g, 5 mg/g, 4 mg/g, 2 mg/g or less.
- the insulin-lipid complex of this invention is applied to the preparation of the insulin-lipid complex to prepare a sustained-release insulin injection.
- the oil solution containing an insulin-lipid complex of this invention is applied to the preparation of a non-injectable formulation such as oral, percutaneous, mucosal, and lung-inhaled insulin.
- the present invention provides a new insulin vesicle, containing an insulin-lipid complex and phospholipids, and can include one or more mixed surfactant such as Tween20, Span60, and the like, the average Particle Size is about 20 nm-200 nm
- the new vesicle containing the insulin-lipid complex of this invention can be an aqueous dispersion, and powder made by freeze drying or spray drying.
- the new vesicle containing the insulin complex of this invention applies to the preparation of non-injectable formulations such as oral, percutaneous, mucosal, and lung-inhaled.
- the complex of the present invention has the following advantages:
- organic solvent system containing low boiling point acid is used as the complex solvent: the complex solvent contains no water, the low boiling point trifluoroacetic acid and hydrogen chloride gas is easy to evaporate, provides an acidic environment for insulin to dissolve and shortens the volatilization time of the organic solvent.
- the selected organic solvent can ensure the complex solution clarification of insulin and lipid material, and the polarity can ensure the compound stability of the insulin and lipid material, which does not affect the mass stability of insulin, obtaining a complex with no acidic material or water residues, the recombination rate is more than 90%, drug content has no obvious changes in the process of preparation and storage.
- the complex significantly improves the lipophilicity of insulin, making the drug distribution in the bilayer membrane of vesicle, markedly improving the stability of the drugs in gastric and intestinal juice, and mucosal transport rate.
- FIG. 1 Graph showing decrease of blood sugar by oil solution containing insulin-lipid complex and new vesicle.
- FIG. 2 Structural diagram of phospholipid complexes and liposome.
- Ethanol and acetone made drug content fall about 5-10%, ether: dropped about 15%, acetic ether, chloroform and tetrahydrofuran fell more markedly, about 30-40%.
- the chemical properties of insulin are relatively stable in the methanol and tetrahydrofuran.
- DMSO and DMF were also investigated. With their high boiling points, it was difficult to dry them by nitrogen flushing, so the freeze drying method was used to remove the solvent, and PBS solution (pH7.4) added to redissolve. After filtration, measurement was performed by HPLC as above to calculate the insulin content, the results showed that insulin content fell markedly in DMF, perhaps related to the alkaline conditions, and DMSO was relatively stable.
- test solution containing 0.1 mg/ml insulin
- the test solution is placed in a quartz cuvette (optical path 0.1 cm) and assayed in the far-ultraviolet region (190 nm ⁇ 250 nm) and the by circular dichromic spectroscopy, and the characteristic peaks and minimum ellipticity of the secondary structure map recorded.
- the other test solution was placed in a 1 cm cuvette, and assayed in the near-ultraviolet region (250 nm ⁇ 350 nm), and the characteristic negative peak and minimum ellipticity of the tertiary structure map recorded.
- the results showed having been treated by three kinds of solvents, the secondary structure map of the insulin showed two negative peaks, at 210 nm and 223 nm, respectively, and minimum ellipticity were ⁇ 10.63 and ⁇ 8.45; the tertiary structure map had a negative peak at 274.5 nm, minimum ellipticity was about ⁇ 2.26.
- the results of the insulin PBS without organic solvent there was no obvious change compared to the untreated insulin PBS, so methanol, tetrahydrofuran and DMSO will not lead to modifications in the spatial structure.
- Glacial acetic acid has a high boiling point, its rotary evaporation is time consuming, and, the concentration of glacial acetic acid becomes more and stronger as the organic solvent volatizes, which causes insulin degradation. In particular, the remaining glacial acetic acid can't be removed in the final complex, harming the storage stability of the complex.
- This kind of complex with its relatively high residual volume of glacial acetic acid still has a marked drop in drug content despite having been dissolve in oil solution, with the content usually dropping in the first 24 hours.
- the inventor has chosen methanol as complex solvent which has no effect on the content of insulin content, added 1-5% glacial acetic acid, to prepare its complex with a drug/phospholipid mass ratio of 1:10, removed the solvent at 35° C. by the rotary evaporation method, dried for 48 hours under vacuum conditions, and assayed the complex.
- the recombination rate was more than 98%, but residues of glacial acetic acid exceeded 0.5% by gas chromatography.
- the complex was stored for 4 weeks at 2-8° C., and compared with the initial content, whereupon the insulin content had fallen about 20%.
- the complex was dissolved in medium chain triglycerides, and placed for 24 hours at room temperature, then compared with the initial content, whereupon the insulin content had fallen about 15%. So, the residual glacial acetic acid had a significant effect on product stability.
- the inventor performed further testing with a methanol solution containing HCl as a reaction solvent and with the distillation method at 35° C. rotary evaporation (temperature is above 50° C. will significantly affect the quality of insulin, so it usually needs to be below 40° C., nor should the time be excessively long), the results showed that, due to the adding of water, it was more difficult to remove the solvent, and complex formation was poor.
- HCl residue was measured at about 0.2% by gas chromatography.
- the complex was stored for 4 weeks at 2-8° C., and thereafter compared with the initial content, the insulin content had fallen about 10%.
- the complex was dissolved in medium chain triglycerides, and placed for 24 hours at room temperature, then compared with the initial content, whereupon the insulin content had fallen about 5%.
- the feed ratios of insulin and soybean phospholipid was 1:1, 1:3, 1:5, 1:7.5, 1:10, 1:15 and 1:20(w/w) respectively.
- the insulin was dissolved in methanol, dichloromethane added to the phospholipids, and mixed.
- the solvent was removed by rotary evaporation with a bath temperature was 37° C., and nitrogen flushing.
- the recombination rate was measured using the solubility of the insulin complex in C6H12, and the insolubility of free insulin in C6H12.
- a suitable volume of the insulin phospholipid complex was accurately weighed out, dissolved in methanol containing 1% glacial acetic acid a suitable volume of the insulin reference substance was dissolved in PBS solution (pH7.4) to prepare a solution (concentration of 1 mg/ml), and diluted in methanol containing 1% glacial acetic acid to make a 0.2 mg/mL solution as the reference solution.
- a suitable volume of the insulin phospholipid complexes (containing about 10 mg insulin) was accurately weighed out, placed in a 10 mL volumetric flask, cyclohexane added, dissolved to constant volume, and shaken, the free insulin which was not compounded was filtered by 0.45 ⁇ m organic membrane, 2 mL of the subsequent filtrate was accurately measured out into a 10 mL volumetric flask, the solvent removed by nitrogen flushing, and methanol containing 1% glacial acetic acid added, dissolved to volume, shaken, and content measured by the above HPLC method, and drug content calculated by the external standard method, and recorded as W composite .
- the recombination rate was calculated according to the following formula:
- a suitable volume of the insulin and phospholipid complex was taken, soybean oil or medium chain Triglycerides added, stirred by a magnetic stirrer at 30° C. for 6 h to mix and dissolve, and placed at 30° C. for 24 h, and observed as to whether the drug was separated out. If no drug was separated out, insulin phospholipid complex was added, and the same operation performed until the drug is separated out. 5 ml were sampled and filtered by 0.45 ⁇ m membrane filtration, and the subsequent filtrate diluted with 1% acetate and methanol as appropriate, measured HPLC, and the apparent solubility in the soybean oil and medium chain triglycerides calculated.
- the content of the drug increases as the insulin drops in the system; when mass ratio of insulin and phospholipids is 1:5, the two compound completely, but if the ratio is above 1:15, the recombination rate enters in a downtrend.
- the solubility increases with the ratio of the phospholipids, and when the ratio is above 1:7.5, the solubility tends towards stability
- the purpose of this invention is to choose the appropriate complex solvent system, improve the compounding efficiency and quality stability of insulin and lipid material.
- the selected solvent system can also meet the following requirements:
- Lipid material and insulin can be dissolved to form a pellucid solution; 2)
- the system contains no water, with low polarity, benefiting intermolecular compounding between insulin and lipid material; 3)
- the solvent system has high evaporation efficiency, and easy vaporization without residual acid or water; 4)
- the insulin properties are stable in the preparation.
- 0.2 g insulin was weighed out and put into a conical flask 9 times, 0.6 g, 1 g, 1.2 g, 1.4 g, 1.6 g, 1.8 g, 2.0 g, 2.4 g and 3.0 g soybean lecithin were added, respectively, then 20 ml methanol solution containing hydrogen chloride gas (concentration 0.1%, weight/volume, g/ml) was added, the mixture was stirred for 10 min at room temperature to dissolve the lipid material and drug to a pellucid solution, which was moved to flasks, and
- the solvent was removed by rotary evaporation, at 35° C., reduced pressure distillation and vacuum drying at room temperature for over 12 hours to obtain 9 groups of complex powders with drug/phospholipid weight ratios of 1:3 ⁇ 1:15.
- 0.2 g insulin was weighed out and put into a conical flask 9 times, and 0.6 g, 1 g, 1.2 g, 1.4 g, 1.6 g, 1.8 g, 2.0 g, 2.4 g and 3.0 g egg yolk lecithin were added, respectively, then 20 ml methanol solution containing hydrogen chloride gas (concentration 0.1%, weight/volume, g/ml) was added, stirred for 10 min at room temperature to dissolve the lipid material and drug to a pellucid solution, which was moved to rotary evaporation flasks, the solvent was removed by rotary evaporation at 35° C., reduced pressure distillation and vacuum drying at room temperature for over 12 hours to obtain 9 groups of complex powders with drug/phospholipid weight ratios of 1:3 ⁇ 1:15.
- hydrogen chloride gas concentration 0.1%, weight/volume, g/ml
- 0.2 g insulin was weighed out and put into a conical flask 9 times, a suitable volume of methanol (containing 0.1%, v/v trifluoroacetic acid) was added to control the concentration of insulin to 10 mg/ml-2 mg/ml, and stirred at room temperature to dissolve the lipid material and drug to a pellucid solution; then 0.6 g, 1 g, 1.2 g, 1.4 g, 1.6 g, 1.8 g, 2.0 g, 2.4 g and 3.0 g soybean lecithin were taken, a suitable volume of dichloromethane (is about 3-6 times the methanol) added, then distilled under reduced pressure in a water bath at 37° C., a suitable volume of dichloromethane was added in the evaporation process (about 1-2 times the methanol), then switched to pump extraction for 10 min
- 0.2 g insulin was weighed out and put into a conical flask 9 times, a suitable volume of methanol (containing 0.1%, v/v trifluoroacetic acid) was added, controlling the concentration of insulin to 10 mg/ml-2 mg/ml, stirred at room temperature to dissolve the lipid material and drug to a pellucid solution, then taking 0.6 g, 1 g, 1.2 g, 1.4 g, 1.6 g, 1.8 g, 2.0 g, 2.4 g and 3.0 g egg yolk lecithin, a suitable amount of dichloromethane (about 3-6 times the methanol) was added, then distilled under reduced pressure in a water bath at 37° C., a suitable volume of dichloromethane was added in the pressure distillation (about 1-2 times the methanol), then switched to pump extraction for 10 min
- 0.2 g insulin was weighed out and put in to a conical flask 8 times, 1 g, 1.2 g, 1.4 g, 1.6 g, 1.8 g, 2.0 g, 2.4 g and 3.0 g sodium deoxycholate were added respectively, then 20 ml tetrahydrofuran solution containing hydrogen chloride gas (concentration 0.1%, weight/volume, g/ml) was added, stirred for 5 min at room temperature and moved to rotary evaporator, and the solvent was removed by rotary evaporation at 35° C., reduced pressure distillation and vacuum drying at room temperature for over 12 hours. 8 groups of complex powder with drug/phospholipid weight ratios of 1:5-1:15 were obtained.
- the 8 groups of complexes were assayed by gas chromatography and all were free of residual hydrogen chloride gas.
- 0.2 g insulin was weighed out and put to a conical flask 9 times, a suitable volume of methanol (containing 0.1%, v/v trifluoroacetic acid) was added, with the concentration of insulin controlled to 10 mg/ml-2 mg/ml, then stirred at room temperature to dissolve lipid material and drug to a pellucid solution then 0.6 g, 1 g, 1.2 g, 1.4 g, 1.6 g, 1.8 g, 2.0 g, 2.4 g and 3.0 g sodium deoxycholate were taken, a suitable amount of dichloromethane (about 3-6 times the methanol) was added, and distilled under reduced pressure in a water bath at 37° C., a suitable volume of dichloromethane was added to distillation (about 1-2 times the methanol), pumping for 10 min after drying.
- methanol containing 0.1%, v/v trifluoroacetic acid
- 0.2 g insulin was weighed out and put to a conical flask 3 times, 2.0 g of soy phosphatidylcholine, egg yolk phosphatidylcholine and sodium deoxycholate were added, and 15 ml DMSO solution containing hydrogen chloride gas (concentration 0.1%, weight/volume, g/ml) was added, stirred at room temperature for 15 min, pre-frozen below ⁇ 40° C. and the solvent was removed by freeze drying, obtaining 3 groups of complexes.
- DMSO solution containing hydrogen chloride gas concentration 0.1%, weight/volume, g/ml
- 0.3 g of the complex was weighed out 5 times, and to each, the following was added: 2.7 g of Glyceryl monooleate, medium chain Triglycerides (medium chain oils), ethyl oleate and isopropyl myristate; the mixture was stirred to dissolve, thereby obtaining an oil solution with 10 mg/g of drug loading capacity, which was then filtered.
- Formulation Composition Formula 1 Formula 2 Formula 3 Formula 4 Complex Example 1 Example 2 Example 3 Example 4 Amount of 110 mg 220 mg 330 mg 550 mg complex Drug loading 1 mg/g 2 mg/g 3 mg/g 5 mg/g capacity Added medium chain oils or long chain oils to 10 g, respectively, to prepare 8 samples
- Oil phase 1 Oil phase 2
- Oil phase 3 MCT 10 g 10 g 10 g Tween 80 1 g 2 g 4 g MCT: Medium Chain Triglycerides
- Said oil solution contained an emulsifier, will be emulsified when 50 times water is added and magnetically stirred for 3 minutes, and the average Particle Size ⁇ 1 ⁇ m after emulsification.
- Oil phase 1 Oil phase 2
- Oil phase 3 MCT 10 g 10 g 10 g Cremphor RH40 1 g 2 g 4 g MCT: Medium Chain Triglycerides
- Said oil solution was stored at room temperature for 24 hours until the solutions were clear and transparent, the residual contents were measured by HPLC, and all were more than 98.6% of the initial amounts, indicating that the drug was not degraded; these were stored at 2-4° C. for 6 months until the solutions were clear and transparent, the residual contents were measured by HPLC, and all were more than 99.2% of the initial amounts, showing stable quality.
- Said oil solution contained an emulsifier, and was emulsified when adding 50 times water and magnetically stirred for 3 minutes, and the average Particle Size was ⁇ 1 nm after emulsion.
- Example 1 to 4 The complexes (with the ratio 1:10, w/w of drug to lipid) of Example 1 to 4 were weighted to 4 groups, oil, emulsifier and co-emulsifier were added based on the following table, the mixture was stirred to dissolve to form self-microemulsion concentrated solution with drug loading capacity of 10 mg/g.
- 4 groups of oil solutions contain emulsifier and co-emulsifier, will be emulsified instantly when adding 5-500 times of the water, HCl or pH6.8 buffer solution, the average Particle Size within 20 ⁇ 50 nm after emulsion determined by laser particle analyzer.
- a suitable amount of the complexes of Examples 1 to 3 (all samples with a drug/lipid ratio of 1:10, w/w) was weighed out to a round-bottom flask, a suitable volume of free phospholipids was added (Free phospholipids content was the same as the phospholipids of the complex), 20 ml dichloromethane was added, and the complexes and phospholipids were dissolved, and vacuum distilled to control the concentration of insulin to 1 mg/mL-10 mg/mL, at a bath temperature of 37° C., and after drying to form a film, 10 m LPBS solution was added to hydrate for 1 h, forming multicellular vesicles, and these were treated by ultrasonic fractionation or High Pressure Homogenization, to form single vesicles with a Particle Size of 50 nm
- Formula Composition Formula 1 Formula 2 Formula 3 Complex (Example Example 1 Example 2 Example 3 1-3) 110 mg 220 mg 550 mg Free phospholipids 100 mg 200 mg 500 mg
- a suitable amount of complexes of Examples 1 to 8 (all samples with a drug/lipid ratio of 1:10, w/w) were weighed out into round-bottom flasks, a suitable amount of free phospholipids was added (Free phospholipids content was the same as phospholipids of the complex), a suitable amount of Tween20 or Span60 surfactant, or a combination thereof, was added, 20 ml dichloromethane was also added, the complexes and phospholipids were dissolved, then vacuum distilled with the insulin concentration controlled to 1 mg/mL-10 mg/mL at a bath temperature of 37° C., a film was formed after drying, 10 m LPBS solution was added to hydrate for lh, forming multicellular vesicles, which were treated by ultrasonic fracturing or High Pressure Homogenization, to form single vesicles with a Particle Size of 50 nm
- Formula Composition Formula 1 Formula 2 Formula 3 Complex (Example Example 1 Example 2 Example 3 1-3) 110 mg 220 mg 550 mg Free phospholipids 100 mg 200 mg 500 mg Tween20 200 mg 400 mg 600 mg
- Formula Composition Formula 1 Formula 2 Formula 3 Complex (Example Example 1 Example 2 Example 3 1-3) 110 mg 220 mg 550 mg Free phospholipids 100 mg 200 mg 500 mg Span60 200 mg 400 mg 600 mg
- test samples were placed in artificial gastric juice containing 1% (weight/volume, g/ml) of protease, incubated in a bath temperature of 37° C., and after vortex blending, 0.5 ml samples were taken at 1 min, 5 min, 30 min and 60 min, add 0.1 ml of cold Tris solution (take Tris reagent 6.07 g, added water to the 500 ml), centrifuge at 10000 RPM, 5 min, and after vortex blending, obtained the supernatant fluid, and the residual percentage of insulin measured by HPLC as above, the results were as follows:
- Test sample insulin solution (INS)
- test samples were placed in artificial gastric juice containing 1% (weight/volume, g/ml) of protease, incubated at a bath temperature of 37° C., and after vortex blending 0.5 ml samples were taken at 1 min, 5 min, 30 min and 60 min, 0.1 ml of cold Tris solution added (take Tris reagent 6.07 g, add water to the 500 ml), centrifuged at 10000 RPM, 5 min, and after vortex blending, the supernatant fluid, and obtained and the residual percentage of insulin measured by HPLC as above, and the results were as follows:
- 0.5 mL of insulin solution of the same concentration was accurately weighed out, the insulin was encapsulated in the same vesicle as the insulin phospholipid complexes (Example 13), moved to 12 WL Caco-2 cells, 1.5 mL HBSS solution was added below the cells as acceptance medium, incubated at a bath temperature of 37° C., and took 200 ⁇ l samples at 30, 60, 120, 180 and 240 min, assayed by the HPLC method, the cumulative permeation amount was calculated, and the results were as follows:
- 35 rats were fasted for a night, but not dehydrated, randomly divided into 5 groups and administered as follows, and blood sugar was examined after the injection.
- the blood sugar percentage of each animal was calculated at each point of time, and the Hypoglycemic effect curve drawn as shown in FIG. 1 , with the hypoglycemic percentage as the Y-axis, and time as the X-axis.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Dispersion Chemistry (AREA)
- Endocrinology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Toxicology (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201010226102 | 2010-07-14 | ||
CNCN201010226102.7 | 2010-07-14 | ||
PCT/CN2011/077152 WO2012006956A1 (zh) | 2010-07-14 | 2011-07-14 | 一种胰岛素的脂质复合物及其制备方法和制剂 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2011/077152 A-371-Of-International WO2012006956A1 (zh) | 2010-07-14 | 2011-07-14 | 一种胰岛素的脂质复合物及其制备方法和制剂 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/895,282 Division US10611852B2 (en) | 2010-07-14 | 2018-02-13 | Insulin-lipid complex, preparation method therefor, and preparation thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US20130338064A1 true US20130338064A1 (en) | 2013-12-19 |
Family
ID=45468937
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/810,098 Abandoned US20130338064A1 (en) | 2010-07-14 | 2011-07-14 | Insulin-lipid complex,preparation method therefor, and preparation thereof |
US15/895,282 Active US10611852B2 (en) | 2010-07-14 | 2018-02-13 | Insulin-lipid complex, preparation method therefor, and preparation thereof |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/895,282 Active US10611852B2 (en) | 2010-07-14 | 2018-02-13 | Insulin-lipid complex, preparation method therefor, and preparation thereof |
Country Status (7)
Country | Link |
---|---|
US (2) | US20130338064A1 (ja) |
EP (1) | EP2594281B1 (ja) |
JP (1) | JP6051157B2 (ja) |
KR (1) | KR101801426B1 (ja) |
CN (3) | CN102512667B (ja) |
CA (1) | CA2805325C (ja) |
WO (1) | WO2012006956A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10611852B2 (en) | 2010-07-14 | 2020-04-07 | Institute Of Materia Medica, Chinese Academy Of Medical Sciences | Insulin-lipid complex, preparation method therefor, and preparation thereof |
WO2022031842A1 (en) * | 2020-08-04 | 2022-02-10 | Reddy Robert R | Polyphenolic insulin |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2511028A (en) * | 2012-12-18 | 2014-08-27 | Univ Manchester Metropolitan | Nano emulsions, methods of forming the same and uses thereof |
CN105617362B (zh) * | 2014-10-27 | 2021-05-11 | 中国医学科学院药物研究所 | 一种新型的胰岛素-磷脂-壳聚糖自组装微粒载体及其制剂 |
CN107308132B (zh) * | 2016-04-26 | 2021-08-17 | 北京五和博澳药业股份有限公司 | 一种磷脂壳聚糖药物递送系统及其制备方法和用途 |
CN106581646A (zh) * | 2016-11-03 | 2017-04-26 | 广州凯耀资产管理有限公司 | 口服胰岛素组合物 |
CN110464835B (zh) * | 2018-05-11 | 2023-06-16 | 中国医学科学院药物研究所 | 一种胰岛素柔性微粒及其制剂 |
CN109498559B (zh) * | 2018-11-30 | 2022-04-12 | 复旦大学 | 一种负载糖尿病治疗多肽的口服制剂及其制备方法 |
CN115389640A (zh) * | 2021-05-25 | 2022-11-25 | 中国医学科学院药物研究所 | 一种胰岛素脂质体药物含量测定方法 |
CN113616798A (zh) * | 2021-09-06 | 2021-11-09 | 天津农学院 | 一种甲苯咪唑脂质复合物、制备方法和应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990011780A1 (en) * | 1989-03-31 | 1990-10-18 | The Regents Of The University Of California | Preparation of liposome and lipid complex compositions |
US5858398A (en) * | 1994-11-03 | 1999-01-12 | Isomed Inc. | Microparticular pharmaceutical compositions |
US6258377B1 (en) * | 1996-07-02 | 2001-07-10 | Provalis Uk Limited | Hydrophobic preparations containing medium chain monoglycerides |
US20080279815A1 (en) * | 1998-10-23 | 2008-11-13 | Idea Ag | Method for developing testing, and using associates of macromolecules and complex aggregates for improved payload and controllable de/association rates |
WO2010060667A1 (en) * | 2008-11-28 | 2010-06-03 | Novo Nordisk A/S | Pharmaceutical compositions suitable for oral administration of derivatized insulin peptides |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL193099C (nl) * | 1981-10-30 | 1998-11-03 | Novo Industri As | Gestabiliseerde insuline-oplossing. |
DD212185A1 (de) * | 1982-12-21 | 1984-08-08 | Adw Ddr | Verfahren zur herstellung von phospholipid-wirkstoff-kombinationen |
GB9323588D0 (en) * | 1993-11-16 | 1994-01-05 | Cortecs Ltd | Hydrophobic preparation |
CN101524349B (zh) * | 2007-09-20 | 2014-01-15 | 中国医学科学院药物研究所 | 双环醇的磷脂复合物及其制备方法 |
CN101380462A (zh) * | 2008-09-04 | 2009-03-11 | 中国药科大学 | 一种新型胰岛素油相溶液的获得方法和制备技术 |
US20130338064A1 (en) | 2010-07-14 | 2013-12-19 | Institute Of Materia Medica, Chinese Academy Of Medical Sciences | Insulin-lipid complex,preparation method therefor, and preparation thereof |
-
2011
- 2011-07-14 US US13/810,098 patent/US20130338064A1/en not_active Abandoned
- 2011-07-14 EP EP11806298.3A patent/EP2594281B1/en active Active
- 2011-07-14 CN CN201110196733.3A patent/CN102512667B/zh active Active
- 2011-07-14 CA CA2805325A patent/CA2805325C/en active Active
- 2011-07-14 JP JP2013518942A patent/JP6051157B2/ja active Active
- 2011-07-14 CN CN201410174195.1A patent/CN104001159B/zh active Active
- 2011-07-14 WO PCT/CN2011/077152 patent/WO2012006956A1/zh active Application Filing
- 2011-07-14 KR KR1020137003805A patent/KR101801426B1/ko active IP Right Grant
- 2011-07-14 CN CN201180002259.4A patent/CN102573889B/zh active Active
-
2018
- 2018-02-13 US US15/895,282 patent/US10611852B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990011780A1 (en) * | 1989-03-31 | 1990-10-18 | The Regents Of The University Of California | Preparation of liposome and lipid complex compositions |
US5858398A (en) * | 1994-11-03 | 1999-01-12 | Isomed Inc. | Microparticular pharmaceutical compositions |
US6258377B1 (en) * | 1996-07-02 | 2001-07-10 | Provalis Uk Limited | Hydrophobic preparations containing medium chain monoglycerides |
US20080279815A1 (en) * | 1998-10-23 | 2008-11-13 | Idea Ag | Method for developing testing, and using associates of macromolecules and complex aggregates for improved payload and controllable de/association rates |
WO2010060667A1 (en) * | 2008-11-28 | 2010-06-03 | Novo Nordisk A/S | Pharmaceutical compositions suitable for oral administration of derivatized insulin peptides |
Non-Patent Citations (4)
Title |
---|
Cui et al. Biodegradable nanoparticles loaded with insulin-phospholipid complex for oral delivery: Preparation, in vitro characterization and in vivo evaluation. Journal of Controlled Release, 2006; 114:242-250 * |
Kisel et al. Liposomes with phosphatidylethanol as a carrier for oral delivery of insulin: studies in the rat. International Journal of Pharmaceutics. 2001; 216:105-114. * |
Kisel et al.Liposomes with phosphatidylethanol as a carrier for oral delivery of insulin: studies in the rat. International Journal of Pharamceutics. 2001; 216:105-114. * |
Sarmento et al. Oral insulin delivery by means of solid lipid nanoparticles. International Journal of Nanomedicine, 2007;2(4): 743-749 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10611852B2 (en) | 2010-07-14 | 2020-04-07 | Institute Of Materia Medica, Chinese Academy Of Medical Sciences | Insulin-lipid complex, preparation method therefor, and preparation thereof |
WO2022031842A1 (en) * | 2020-08-04 | 2022-02-10 | Reddy Robert R | Polyphenolic insulin |
Also Published As
Publication number | Publication date |
---|---|
CA2805325C (en) | 2020-08-04 |
EP2594281A1 (en) | 2013-05-22 |
US10611852B2 (en) | 2020-04-07 |
KR101801426B1 (ko) | 2017-12-20 |
CN102512667A (zh) | 2012-06-27 |
CN102512667B (zh) | 2015-08-19 |
WO2012006956A1 (zh) | 2012-01-19 |
EP2594281A4 (en) | 2014-02-26 |
KR20130043193A (ko) | 2013-04-29 |
EP2594281B1 (en) | 2019-08-28 |
CN102573889A (zh) | 2012-07-11 |
CN104001159B (zh) | 2016-08-24 |
JP6051157B2 (ja) | 2016-12-27 |
CN102573889B (zh) | 2014-10-22 |
JP2013531015A (ja) | 2013-08-01 |
CN104001159A (zh) | 2014-08-27 |
CA2805325A1 (en) | 2012-01-19 |
US20180171031A1 (en) | 2018-06-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10611852B2 (en) | Insulin-lipid complex, preparation method therefor, and preparation thereof | |
JP5908847B2 (ja) | インスリンペプチドを経口投与するための医薬組成物 | |
US20110293714A1 (en) | Pharmaceutical compositions suitable for oral administration of derivatized insulin peptides | |
KR980008239A (ko) | 사이클로스포린-함유 약학적 조성물 | |
CN102218035A (zh) | 埃索美拉唑钠脂质体组合药物配方及制备方法和用途 | |
US20130150335A1 (en) | Paclitaxel/steroidal complex | |
CN108938566B (zh) | 细辛脑自乳化系统 | |
WO2008022557A1 (fr) | Composition liquide de sirolimus | |
CN102113996A (zh) | 一种含有蛋白质或多肽的口服制剂、其制备方法及用途 | |
CN111643451B (zh) | 一种注射用和厚朴酚自乳化微乳制剂及其制备方法 | |
JP2942556B2 (ja) | シクロスポリンを含有する新規組成物 | |
CN101411685A (zh) | 一种静脉麻醉药2,6-二异丙基苯酚微乳组合物及其制备方法 | |
CN102008713A (zh) | 环孢素a前体脂质体、药物组合物及其制备方法 | |
CN115429756B (zh) | 一种阿苯达唑脂质复合物及其制备方法和应用 | |
CN101380462A (zh) | 一种新型胰岛素油相溶液的获得方法和制备技术 | |
CN104055749B (zh) | 环孢素a的自微乳化软胶囊内容物组合及其制备方法 | |
WO2024153103A1 (zh) | 一种包含水飞蓟宾的白蛋白组合物及其制备方法 | |
El-laithy et al. | Design and hepatoprotective evaluation of biphenyl dimethyl dicarboxylate (DDB) and silymarin solid dispersion and self-micro emulsifying drug delivery systems | |
CN107362144A (zh) | 一种鲁拉西酮脑靶向脂质体注射剂及其制备方法 | |
CN115389640A (zh) | 一种胰岛素脂质体药物含量测定方法 | |
CN102423483A (zh) | 一种复方雷米普利纳米乳抗高血压药物 | |
CN118304279A (zh) | 一种骨化三醇自微乳口溶膜及其制备方法 | |
KR19990047897A (ko) | 사이클로스포린 함유 약학적 조성물 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF ME Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LIU, YULING;ZHOU, CUIPING;SONG, ZHIHUI;AND OTHERS;REEL/FRAME:031126/0591 Effective date: 20130301 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |