CN104586768A - Linezolid-containing anti-infection pharmaceutical composition and preparation method thereof - Google Patents

Abstract

The invention discloses an anti-infection medicinal composition containing linezolid and a preparation method thereof. The pharmaceutical composition contains 1.0-5.0% (g/ml) of linezolid, and is composed of ethosome drug-carrying system and aqueous gel system; it can be made into linezolid ethosome gel spray, which can be used for Topical anti-infective treatment.

Description

A kind of anti-infection medicinal composition containing linezolid and preparation method thereof

technical field

The invention provides an anti-infection pharmaceutical composition containing linezolid and a preparation method thereof, belonging to the technical field of drug delivery systems.

Background technique

Skin bacterial infection, that is, bacterial infectious skin disease, is clinically manifested as skin furuncle, gangrene, cellulitis, folliculitis, etc. The strains causing skin infection are mainly Gram-positive bacteria, accounting for 84.7% of the total isolates, and Staphylococcus accounts for 94.4% of Gram-positive bacteria, of which Staphylococcus aureus accounts for 63.9%, so Staphylococcus, especially Staphylococcus aureus Bacteria are considered the main pathogens causing skin infections.

Staphylococcus aureus is also the main pathogen of nosocomial infection and community infection. It is highly pathogenic and can cause various infections such as sepsis, catheter-derived infection, wound infection, systemic infection, and toxic shock syndrome.

Skin diseases also account for a high proportion of nosocomial infections due to the pathology of the disease itself and the characteristics of the diseased site. In recent years, with the widespread use of antibacterial drugs, drug-resistant bacteria have spread rapidly. Methicillin-resistant Staphylococcus aureus The increase of (MRSA) has brought many problems to the clinical treatment of skin infections, especially patients with burns, scalds and severe skin diseases, who are more susceptible to the invasion and infection of MRSA. Anti-drug-resistant bacterial infection drugs with good compliance have also become a thorny issue.

Linezolid is a fully synthetic oxazolidinone antibacterial drug with the chemical name N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl] -2-oxo-5-oxazolyl]methyl]-acetamide, the chemical structural formula is as follows:

Linezolid has good activity against all positive bacteria, including methicillin-sensitive or resistant Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus pyogenes, Staphylococcus pneumoniae, Streptococcus agalactiae and Enterococcus. Linezolid injection and oral tablets are currently on the market. However, in the treatment of skin infections, oral administration has disadvantages such as gastrointestinal adverse reactions and hepatic first pass effect; intravenous administration has disadvantages such as low safety factor, inconvenient administration and poor compliance. The skin topical preparations are more suitable for the treatment of skin infections with linezolid because of their convenient application, low adverse reactions, high safety factor, and good compliance.

In view of the above requirements, there is a need for a pharmaceutical composition containing linezolid that can be used externally on the skin, and the composition should be able to meet the needs of local administration concentration to exert anti-infective effects, and at the same time, this composition should meet the requirements of non-toxicity. To meet the requirements of toxicity, non-irritation, and skin tolerance, it should be as convenient as possible, durable in efficacy, and good in compliance.

Because the solubility of linezolid in water is very small, it is only slightly soluble in water, and the solubility in water at room temperature is less than 3 mg/ml, so it is difficult to prepare a higher concentration of water-based preparations. In order to meet the clinical needs of high-concentration linezolid-containing topical preparations, increasing its solubility in the aqueous system is one of the key issues that need to be solved. In addition, promoting the transdermal absorption of the drug is another key issue that needs to be solved. .

Biological nanomaterials, such as liposomes, polymer micelles, ethosomes, etc., can solubilize insoluble drugs through encapsulation. Due to the characteristics of safety, non-irritation, and good biocompatibility, such biomaterials have become a research hotspot as drug carriers in recent years. Among them, ethosomes (Ethosomes) are a new type of liposomes. The presence of alcohol improves the solubility of lipophilic and amphiphilic substances in the phosphatidylcholine bilayers and aqueous centers of vesicles, and is compatible with polymer micelles and Compared with ordinary liposomes, they have the advantages of smaller particle size, more flexibility, and easier penetration into the deep layer of the skin, and are more suitable for skin drug delivery systems. Etosomes and other bio-nanomaterials have attracted widespread attention due to their good biocompatibility, and their stability is also a major reason for the limited development of such drug delivery systems. Wang Jun et al. (Chinese Pharmacist, 2012, 15 (6), 780-782.) Introduce the aqueous gel system into the ketoprofen ethosome system, so that the ethosomes are distributed in the three-dimensional network structure of the gel, and the stability is enhanced.

The anti-infective pharmaceutical composition containing linezolid and the pharmaceutical preparation prepared by the preparation method provided by the present invention use ethosomes to wrap linezolid to play a role in solubilization, so as to improve the concentration of linezolid At the same time, the alcohol contained in the ethosome acts as a skin penetration enhancer, which can promote the percutaneous absorption of the drug; and the three-dimensional network structure formed by the gel matrix can not only enhance the stability of the etosome, Reach the purpose of medicine slow release again. Another innovation of the present invention is that the ethosome gel containing high-concentration linezolid is made into a spray, which makes it more suitable for the administration of skin infections and has good applicability to patients.

The anti-infective pharmaceutical composition containing linezolid provided by the present invention and the pharmaceutical preparation prepared by the preparation method thereof can meet the following requirements: (1) the concentration of linezolid is significantly higher than that of isotonic aqueous solution; Maximum solubility to ensure topical administration as needed. (2) Sterile. Ordinary multiple-dose medication requires the addition of preservatives to ensure sterility; severe infections, burns and scald infections require that the drugs must be used aseptically at one time. (3) Appropriate pH. Conforms to skin acceptable pH range to reduce skin irritation. (4) Burn and scald wounds are extremely sensitive. To avoid pain and discomfort, non-contact administration should be used as much as possible. (5) Appropriate osmotic pressure. (6) Appropriate viscosity. Appropriate viscosity can increase the residence time of the drug on the skin surface and promote the percutaneous absorption of the drug, while too high a viscosity will affect the application of the drug. (7) Good biocompatibility, non-toxic, non-irritating, good compliance and convenient drug administration.

Contents of the invention

The object of the present invention is to provide an anti-infection medicinal composition containing linezolid and a preparation method thereof. The composition can be used for external medicine of bacterial infection caused by skin wounds, burns, scalds, etc., as well as nosocomial skin infections, etc., and has good patient compliance.

The invention provides an anti-infective pharmaceutical composition containing linezolid, which uses ethosomes to encapsulate linezolid, and the gel system receives unencapsulated free part of the drug to increase the drug loading capacity of the aqueous system, so that the combination The main drug content of linezolid in the product is 1.0-5.0% (g/ml).

The invention provides a linezolid-containing anti-infection pharmaceutical composition containing 1.0-5.0% (g/ml) of the linezolid, and consists of an ethosome drug-carrying system and an aqueous gel system.

Etosome is a special liposome, on the basis of the main components such as phosphatidylcholine and cholesterol, a certain amount of alcohol is added to promote the percutaneous absorption of drugs.

The alcohol used in the ethosomes in the above composition can generally be selected from one or both of ethanol and propylene glycol. However, considering that the composition is used for serious skin infection and burn and scald skin infection, in order to avoid potential stimulation, the present invention determines to use propylene glycol. The addition of alcohol can increase the formation of small multivesicular etosomes to a certain extent, and indirectly increase the encapsulation efficiency, but too much propylene glycol will affect the viscosity of the pharmaceutical composition, and too much propylene glycol will also reduce the encapsulation of etosomes Rate. The present invention screens the dosage of propylene glycol by taking ethosome encapsulation rate, stability and viscosity as indexes, and the optimal dosage is 5-30%, and the optimal dosage is 10-20%.

The lipid components used in the ethosomes in the above composition are selected from phosphatidylcholine and cholesterol. Among them, phosphatidylcholine forms a lipid membrane, and cholesterol, as an amphipathic molecule, can be embedded in the membrane to help stabilize the structure of liposomes. When cholesterol reaches a certain concentration, it can stabilize the lipid membrane. However, too much cholesterol will affect the formation of bilayer membranes and reduce the stability of liposomes. Therefore, the present invention takes the stability of the blank ethosome as an index, places the blank ethosome at room temperature and under accelerated conditions for a period of time, observes the transparency, layering, turbidity and precipitation during the placement process, and screens the phospholipid Acylcholine-cholesterol dosage ratio, the optimal dosage ratio is 6:1-2:1, and the optimal dosage ratio is 4:1-3:1.

For the ethosome of the above composition, the important indexes are encapsulation efficiency and drug loading capacity. The ratio of drug to phosphatidylcholine directly affects the encapsulation efficiency and drug loading concentration of the drug. When the drug-to-lipid ratio was low, the encapsulation efficiency of ethosomes was high, but the drug loading was low. With the increase of drug-lipid ratio, the encapsulation efficiency of ethosomes decreased, but the drug-loading capacity increased. When the drug-to-lipid ratio is too large, too much drug will affect the formation of ethosomes and affect the encapsulation. The present invention considers the two indexes of encapsulation efficiency and drug loading, sets the ratio of drug-phosphatidylcholine, and preliminarily investigates 1:2, 1:4, 1::6, 1:16, 1:32, The encapsulation efficiency and drug loading of ethosomes at a ratio of 1:64, the optimal ratio is 1:4 to 1:16, and the optimal ratio is further screened to be 1:5 to 1:8.

The ethosome in the above composition comprises the following components:

(1) The listed drug is linezolid;

(2) The lipid membrane is composed of phosphatidylcholine and cholesterol;

(3) The organic phase is selected from one or more of chloroform, ethyl acetate, methanol, ethanol, and dimethyl sulfoxide;

(4) The alcohol substance is propylene glycol;

(5) Its water phase is the phosphate buffer saline of pH6.8;

(6) The antioxidant is one of vitamin E and vitamin C.

The ethosome in the above-mentioned composition, its preparation method is:

① Weigh the prescribed amount of linezolid, phosphatidylcholine, and cholesterol, dissolve them with the prescribed amount of organic phase, place them in a ground-mouth rotary evaporator flask, and remove the organic phase by rotary evaporation in a constant temperature water bath at 40°C under reduced pressure;

②At 40°C, add an appropriate amount of glass beads to a ground-mouth rotary evaporating flask, add the prescribed amount of pH 6.8 phosphate buffer solution and the prescribed amount of alcohol solution, rotate and stir for 20 minutes, and hydrate to form ethosomes;

③ Remove the glass beads from the above mixture, add the prescribed amount of antioxidant, and shake evenly;

④ The above mixed solution is properly ultrasonicated to reduce the particle size of ethosomes;

⑤ Pass the above solution through a 0.22 μm microporous membrane to obtain sterile linezolid ethosomes.

The particle size of the ethosome prepared by the above method is controlled between 50-220nm. Among them, ultrasound can reduce the particle size of the initial etosomes, and at the same time, it can transform part of the initially formed multilayer etosomes into single-chamber etosomes. The particle size of the etosomes obtained by this treatment is uniform and small, which is more conducive to drug loading .

The gel system included in the above composition is an aqueous gel.

The aqueous gel of the above composition has a gel base selected from one of carbomer and polycarbophil. Since the linezolid ethosome gel of the present invention is finally prepared into a spray, it is considered that the pharmaceutical composition must meet a certain viscosity, thereby prolonging the action time of the drug on the skin surface, and ensuring that the drug is released from the spray device. After being ejected smoothly, the present invention screens the dosage of the gel matrix, preferably the dosage range is 0.2-0.6%, and the optimal dosage is 0.3-0.5%.

In the aqueous gel of the above composition, the wetting agent is poloxamer. Poloxamers act as surfactants to increase the apparent solubility of the drug. Poloxamer 407 is a water-soluble surfactant, which is more suitable for gels, emulsions and ointments. Therefore, the present invention chooses poloxamer 407. In addition, another purpose of selecting poloxamer in the present invention is that it has thermosensitivity, and its thermosensitivity has been studied, and the optimal dosage has been screened. The research results show that when the concentration of poloxamer 407 is greater than 0.5%, it begins to show thermosensitivity, that is, the viscosity increases with the increase of temperature. Combined with the degree of its viscosity changing with temperature, it is determined that its optimal dosage is 0.5%-2%, and the optimal dosage is 1.0-1.5%.

For the aqueous gel in the above composition, the pH adjuster is sodium hydroxide or hydrochloric acid; the preservative is selected from benzalkonium chloride and benzalkonium bromide, and the dosage is 0.01-1.0%.

The aqueous gel in the above-mentioned composition, its preparation method is:

① Weigh the gel matrix of the prescribed amount, fully swell overnight with an appropriate amount of water for injection, add 1mol/L sodium hydroxide to adjust the pH to 5.0-7.0 to make it into a gel;

② Add the prescribed amount of poloxamer and preservatives, and stir evenly with a vacuum emulsifier;

③ Sterilize at 121°C for 12 minutes, and cool to obtain a sterile blank gel.

Under sterile conditions, mix the sterile linezolid ethosome with the sterile blank aqueous gel, add water for injection to the full amount, and stir evenly with a vacuum emulsifier to obtain the linezolid ethosome gel.

Under aseptic conditions, the above-mentioned linezolid ethanol gel composition is potted in a sterilized and dried manual spray device to obtain the linezolid ethanol gel spray.

Detailed ways

The following typical embodiments are used to illustrate the present invention. Simple replacements or improvements made by those skilled in the art are within the technical solutions protected by the present invention.

Example 1:

Alcohol Prescription:

Gel Base Prescription:

Preparation Process:

(1) Preparation of sterile linezolid ethosomes:

①Weigh the prescribed amount of linezolid, phosphatidylcholine, and cholesterol, dissolve them with the prescribed amount of dimethyl sulfoxide, place them in a ground-mouth rotary evaporator, and remove the dimethyl sulfoxide by rotary evaporation in a constant temperature water bath at 40°C under reduced pressure. Sulfone;

②At 40°C, add an appropriate amount of glass beads to the ground-mouth rotary evaporating flask, add the prescribed amount of pH6.8 phosphate buffer solution and the prescribed amount of propylene glycol solution, and rotate and stir for 20 minutes;

③Remove the glass beads from the above mixture, add the prescribed amount of vitamin E, oscillate evenly, and use appropriate ultrasound;

④ The above mixture was passed through a 0.22 μm microporous membrane to obtain sterile linezolid ethosomes.

(2) Preparation of sterile blank gel:

① Weigh the prescribed amount of polycarbophil, fully swell overnight with an appropriate amount of water for injection, add 1 mol/L sodium hydroxide solution to adjust the pH to 5.0-7.0, and make a gel;

② Add the prescribed amount of poloxamer 407 to the above gel, and stir with a vacuum emulsifier;

③ Dilute the prescribed amount of benzalkonium bromide with a small amount of purified water and add it to the above mixture, and stir evenly with a vacuum emulsifier;

④ Sterilize at 121°C for 12 minutes, and cool to obtain a sterile blank gel.

(3) Preparation of linezolid ethosome gel spray:

Under sterile conditions, mix sterile linezolid ethosome and sterile blank gel at a volume ratio of 1:1, add water for injection to the full amount, and stir evenly with a vacuum emulsifier to obtain 2% linezolid Amine ethosome gel.

Under sterile conditions, the above-mentioned linezolid ethosome gel composition is potted in a sterilized and dried manual spray device to obtain the linezolid ethosome gel spray.

Example 2:

Alcohol Prescription:

Gel Base Prescription:

Preparation Process:

(1) Preparation of sterile linezolid ethosomes:

① Weigh the prescribed amount of linezolid, phosphatidylcholine, and cholesterol, dissolve them in the prescribed amount of chloroform, place them in a ground-mouth rotary evaporator, and remove the chloroform by rotary evaporation in a constant temperature water bath at 40°C under reduced pressure;

②At 40°C, add an appropriate amount of glass beads to the ground-mouth rotary evaporating flask, add the prescribed amount of pH6.8 phosphate buffer solution and the prescribed amount of propylene glycol solution, and rotate and stir for 20 minutes;

③Remove the glass beads from the above mixture, add the prescribed amount of vitamin C, oscillate evenly, and sonicate appropriately;

④ Pass the above solution through a 0.22 μm microporous membrane to obtain sterile linezolid ethosomes.

(2) Preparation of sterile blank gel:

① Weigh the prescribed amount of carbomer, fully swell overnight with an appropriate amount of water for injection, add 1mol/L sodium hydroxide to adjust the pH to above 4.5, and make it into a gel;

② Add the prescribed amount of poloxamer 407 to the above gel, and stir with a vacuum emulsifier;

③ Dilute the prescribed amount of benzalkonium chloride with a small amount of purified water and add it to the above mixture, and stir evenly with a vacuum emulsifier;

④ Sterilize at 121°C for 12 minutes, and cool to obtain a sterile blank gel.

(3) Preparation of linezolid ethosome gel spray:

Under sterile conditions, mix sterile linezolid ethosome and sterile blank gel at a volume ratio of 1:1, add water for injection to the full amount, and stir evenly with a vacuum emulsifier to obtain 3% linezolid Amine ethosome gel.

Under sterile conditions, the above-mentioned linezolid ethosome gel composition is potted in a sterilized and dried manual spray device to obtain the linezolid ethosome gel spray.

Example 3:

Alcohol Prescription:

Gel Base Prescription:

Preparation Process:

(1) Preparation of sterile linezolid ethosomes:

① Weigh the prescribed amount of linezolid, phosphatidylcholine, and cholesterol, dissolve in the prescribed amount of ethyl acetate, place in a ground-mouth rotary evaporator, and remove chloroform by rotary evaporation in a constant temperature water bath at 40°C under reduced pressure;

②At 40°C, add an appropriate amount of glass beads, the prescribed amount of phosphate buffer solution and the prescribed amount of propylene glycol solution into the ground-mouth rotary evaporating flask, and rotate and stir for 20 minutes;

③Remove the glass beads from the above mixture, add the prescribed amount of vitamin C, oscillate evenly, and sonicate appropriately;

④ Pass the above solution through a 0.22 μm microporous membrane to obtain sterile linezolid ethosomes.

(2) Preparation of sterile blank gel:

① Weigh the prescribed amount of polycarbophil, fully swell overnight with an appropriate amount of water for injection, add 1mol/L sodium hydroxide solution to adjust the pH to above 4.5, and make it into a gel;

② Add the prescribed amount of poloxamer 407 to the above gel, and stir in a vacuum emulsifier;

③ Dilute the prescribed amount of benzalkonium chloride with a small amount of purified water and add it to the above mixture, and stir evenly with a vacuum emulsifier;

④ Sterilize at 121°C for 12 minutes, and cool to obtain a sterile blank gel.

(3) Preparation of linezolid ethosome gel spray:

Under sterile conditions, mix sterile linezolid ethosome and sterile blank gel at a volume ratio of 1:1, add water for injection to the full amount, and stir evenly with a vacuum emulsifier to obtain 4% linezolid Amine ethosome gel.

Under sterile conditions, the above-mentioned linezolid ethosome gel composition is potted in a sterilized and dried manual spray device to obtain the linezolid ethosome gel spray.

Claims (13)

1., containing the infection Pharmaceutical composition of Linezolid, it is characterized in that the Linezolid comprising concentration range 1.0 ~ 5.0% (g/ml), and ethosome medicine-carried system and aqueous gel medicine-carried system.

2. Pharmaceutical composition according to claim 1, is characterized in that the lipid components that described ethosome uses selects phosphatidylcholine and cholesterol.

3. the Pharmaceutical composition according to claim 1 and 2, it is characterized in that the more excellent usage ratio of phosphatidylcholine-cholesterol that described ethosome uses is 6:1 ~ 2:1, optimum usage ratio is 4:1 ~ 3:1.

4. Pharmaceutical composition according to claims 1 to 3, it is characterized in that the more excellent usage ratio of the drug-phospholipid phatidylcholine of described medicine carrying ethosome is 1:4 ~ 1:16, optimum usage ratio is 1:5 ~ 1:8.

5. Pharmaceutical composition according to claims 1 to 4, it is characterized in that the alcohol used in described ethosome is propylene glycol, its more excellent consumption is 5 ~ 30%, and optimum consumption is 10 ~ 20%.

6. Pharmaceutical composition according to claims 1 to 5, is characterized in that described ethosome comprises following composition:

(1) contained medicine is Linezolid;

(2) lipid film is made up of phosphatidylcholine, cholesterol;

(3) organic facies is selected from one or more in chloroform, ethyl acetate, methanol, ethanol, dimethyl sulfoxide;

(4) its alcohols material is propylene glycol;

(5) its aqueous phase is the phosphate buffer of pH6.8;

(6) its antioxidant is the one in vitamin E, vitamin C.

7. Pharmaceutical composition according to claims 1 to 6, is characterized in that the preparation method of described ethosome is:

1. take the Linezolid of recipe quantity, phosphatidylcholine, cholesterol, dissolve by the organic facies of recipe quantity, be placed in ground rotary evaporation bottle, 40 DEG C of water bath with thermostatic control decompression rotary evaporation removing organic faciess;

2. under 40 DEG C of conditions, add appropriate bead by ground rotary evaporation bottle, add the phosphate buffer of the pH6.8 of recipe quantity and the alcoholic solution of recipe quantity, Stirring 20min, aquation forms ethosome;

3. above-mentioned mixed liquor removing bead, add the antioxidant of recipe quantity, concussion is evenly;

4. above-mentioned mixed liquor is suitably ultrasonic, to reduce ethosome particle diameter;

5. above-mentioned solution crosses 0.22 μm of microporous filter membrane, obtains aseptic Linezolid ethosome.

8. Pharmaceutical composition according to claim 1, it is characterized in that the one described aqueous gel substrate be selected from carbomer, polycarbophil, its more excellent amount ranges is 0.2 ~ 0.6%, and optimum consumption is 0.3 ~ 0.5%.

9. the Pharmaceutical composition according to claim 1 and 8, it is characterized in that the wetting agent used in described aqueous gel system selects poloxamer188, its more excellent consumption is 0.5% ~ 2%, and optimum consumption is 1.0 ~ 1.5%.

10. the Pharmaceutical composition according to claim 1 and 8 ~ 9, is characterized in that the antiseptic used in aqueous gel system is selected from the one in benzalkonium chloride, benzalkonium bromide, and consumption is 0.01 ~ 1.0%.

11. Pharmaceutical compositions according to claim 1 and 8 ~ 10, is characterized in that described aqueous gel preparation method is:

1. take the gel-type vehicle of recipe quantity, spend the night with appropriate water for injection is fully swelling, add 1mol/L sodium hydroxide and adjust pH to 5.0 ~ 7.0 to make gel;

2. add the poloxamer188 of recipe quantity, antiseptic, vacuum emulsifying machine stirs;

3. through 121 DEG C of sterilizings 12 minutes, aseptic Blank gel is cooled to obtain.

12. according to the Pharmaceutical composition described in claim 1 ~ 11, it is characterized in that aseptically, aseptic Linezolid ethosome is mixed with aseptic blank aqueous gel, then adds to the full amount of water for injection, vacuum emulsifying machine stirs, and obtains Linezolid Ethosomal gel compositions.

13. according to the Pharmaceutical composition described in claim 1 ~ 12, it is characterized in that aseptically, by the hand spray device of Linezolid Ethosomal gel compositions embedding in sterilizing-drying, obtains Linezolid Ethosomal gel spray.