CN113440529A

CN113440529A - Injectable pharmaceutical composition and preparation method thereof

Info

Publication number: CN113440529A
Application number: CN202110317250.8A
Authority: CN
Inventors: 于立霞; 孙琼; 李金宇; 齐晓雪; 刘廷; 卢韵
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2020-03-25
Filing date: 2021-03-25
Publication date: 2021-09-28
Anticipated expiration: 2041-03-25
Also published as: CN113440529B

Abstract

The present disclosure relates to an injectable pharmaceutical composition and a method of preparing the same. In particular, the pharmaceutical compositions described in the present disclosure comprise rilpivirine nanoparticles and a surface stabilizer. The pharmaceutical composition provided by the disclosure relates to the application of the pharmaceutical composition in the treatment and prevention of HIV infection, has good stability, and is suitable for industrial production.

Description

Injectable pharmaceutical composition and preparation method thereof

Technical Field

The disclosure relates to the field of pharmaceutical preparations, in particular to an injectable pharmaceutical composition containing nanoparticles of rilpivirine and a preparation method thereof.

Background

Acquired Immune Deficiency Syndrome (AIDS) is caused by the Human Immunodeficiency Virus (HIV) which is feared in that it targets the most important CD 4T lymphocyte in the human immune system as a major attack, destroying it in large quantities, and depriving the human body of immune function. Treatment compliance and pubic sympathy remain major obstacles to combating the HIV-1 epidemic. In China, AIDS has already entered a rapid growth period, and the epidemic development trend is severe. Therefore, the search for effective treatments for aids has become a major and worldwide concern.

Rilpivirine is white to white-like powder, has a diaryl pyrimidine structure, can be tightly allosterically combined with reverse transcriptase of HIV-1, is used as a strong non-nucleoside reverse transcriptase inhibitor (NNRTI), intervenes in the early stage of virus HIV replication cycle, and prevents virus DNA synthesis and subsequent integration of virus genome in host DNA; compared with other non-nucleoside reverse transcriptase inhibitors (efavirenz), rilpivirine has the advantages of small nerve and metabolic side effects and good tolerance. The currently marketed rilpivirine tablets have the specification of 25 mg/tablet, and are orally taken by patients one tablet per day, so that the rilpivirine tablets have obvious food effect and need to be taken after a meal. Because rilpivirine raw material has poor water solubility and oil solubility, the bioavailability of the tablet is low, and the rilpivirine raw material is sometimes required to be combined with other anti-AIDS drugs.

Other anti-HIV drugs currently in use require frequent administration of relatively high doses (efavirenz (600 mg/day), lamivudine (300 mg/day)), frequency of intake, and number and volume of administrations increase the risk of patients not taking the full dose and thereby failing to comply with the prescribed dosage regimen. This not only reduces the effectiveness of the treatment but also results in the development of viral resistance, and it is therefore necessary to design an anti-HIV therapy that does not require frequent dosing. The rilpivirine nanocrystal has obvious clinical advantages, does not need carrier materials, only needs a small amount of stabilizing agents, has no toxicity problems (such as hemolysis, anaphylactic reaction and the like) caused by excipients, is not limited by encapsulation rate and drug-loading rate, and can meet the requirements of high-dose and high-concentration preparations. The rilpivirine nano particles prepared can be used as a preparation storage, is slowly dissolved and absorbed by a human body, and is applied at long time intervals, such as one month or more, so as to achieve the effects of preventing and treating HIV for a long time.

CN101478950A discloses a pharmaceutical composition comprising rilpivirine in nanoparticle form, a surface modifying agent and a pharmaceutically acceptable carrier. CN108210469A discloses a pharmaceutical composition comprising rilpivirine, a surfactant and a lyoprotectant. CN101636149B discloses a supersaturated solution comprising rilpivirine and a water soluble polymer selected from polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, a hydroxyalkyl alkylcellulose, and a poloxamer, in an aqueous medium. WO2015136294a1 discloses pharmaceutical compositions comprising rilpivirine in nanoparticulate form and one or more pharmaceutically acceptable excipients.

Disclosure of Invention

The present disclosure provides a pharmaceutical composition comprising rilpivirine nanoparticles and a surface stabilizer, wherein the surface stabilizer comprises a first surface stabilizer polyethylene glycol stearate or a derivative thereof and a second surface stabilizer selected from one or more of sodium deoxycholate, sodium cholate, sodium hydroxymethylcellulose, sodium docusate, preferably one or more of sodium deoxycholate, sodium hydroxymethylcellulose, more preferably sodium deoxycholate.

The polyethylene glycol stearate or derivatives thereof of the present disclosure include, but are not limited to, polyethylene glycol-660-hydroxystearate, polyethylene glycol-15-hydroxystearate, polyethylene glycol-400-monostearate, polyoxyethylene castor oil derivatives (including, but not limited to Cremophor EL, Cremophor RH40, Cremophor RH60), and the like, preferably polyethylene glycol 15-hydroxystearate.

The pharmaceutical composition of the present disclosure comprises rilpivirine nanoparticles, a first surface stabilizer, a second surface stabilizer, and may further comprise additional surface stabilizers, pH modifiers, antioxidants, photolytic agents, emulsifiers, lyoprotectants, bacteriostatic preservatives, isotonic adjusting agents, sedimentation inhibitors, liquid media, and the like.

The surfactant can be nonionic, anionic, cationic and zwitterionic compound or surfactant, and is selected from one or more of polyvidone, polyoxyethylene sorbitan fatty acid ester, sodium deoxycholate, polyethylene glycol stearate, poloxamer, 15-hydroxystearic acid polyethylene glycol ester, polyvinyl alcohol, docusate sodium, hydroxypropyl methylcellulose, lecithin, sodium cholate, and hydroxymethyl cellulose sodium. Non-ionic surface stabilizers described in the present disclosure include, but are not limited to, Hydroxypropylmethylcellulose (HPMC), povidone, poloxamer, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol stearate, polyethylene glycol 15-hydroxystearate. Anionic surface stabilizers described in the present disclosure include, but are not limited to, sodium dioctyl succinate (DOSS), sodium docusate, sodium cholate, sodium deoxycholate, and sodium hydroxymethyl cellulose. The cationic surface stabilizers described in this disclosure include, but are not limited to, polymers, biopolymers, poly-N-methylpyridinium, pyridinium sulfate chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polystyrene, polymethylmethacrylate trimethylammonium bromide (PMMTMABr), hexylmethyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethylmethacrylate dimethyl sulfate. The zwitterionic surface stabilizers described in this disclosure include, but are not limited to, proteins, phospholipids, zwitterionic polymers, and zwitterionic surfactant molecules, which can be, for example, phosphatidylcholine, lecithin, gelatin, and the like. The surface stabilizer described in the present disclosure includes not only the surface stabilizer described above in the conventional sense but also some additives equivalent to the above surface stabilizer, for example, a mixture of deoxycholic acid and sodium phosphate is equivalent to sodium deoxycholate.

Wherein the pH regulator includes but is not limited to hydrochloric acid, sulfuric acid, lactic acid, malic acid, acetic acid, citric acid, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium dihydrogen phosphate, sodium citrate, arginine, etc.; antioxidants include, but are not limited to, L-cysteine hydrochloride, sodium sulfite, sodium bisulfite, propyl gallate, glutathione, sodium thiosulfate, vitamin E, thiourea, and the like; lyoprotectants include, but are not limited to, mannitol, arginine, povidone, dextran, and the like, and isotonicity adjusting agents include, but are not limited to, sodium chloride, glucose, sorbitol, phosphate, sodium citrate, and the like; sedimentation inhibitors include, but are not limited to, mannitol, dextrose sucrose, polyethylene glycol, dextran 40, trehalose, glycerol, povidone, glycine, hydroxypropyl- β -cyclodextrin, and the like; liquid media include, but are not limited to, water, saline solution, safflower seed oil, ethanol, t-butanol, hexane, ethylene glycol, and the like.

The nanoparticles may be prepared by co-milling, high pressure homogenization or anti-solvent methods, with co-milling being preferred. The liquid medium used for co-milling is selected from the group consisting of water, saline solution, safflower seed oil, ethanol, t-butanol, hexane and ethylene glycol, preferably water, saline solution, safflower seed oil, most preferably water or saline solution. One embodiment of the present disclosure is to co-grind rilpivirine and a surface stabilizer to obtain nanoparticles using water as a liquid medium.

The weight ratio of the surface stabilizer to the rilpivirine is 1: 0.01-1: 100, preferably 1: 1-1: 80, more preferably 1: 5-1: 30, and most preferably 1: 6.5-1: 20.

The weight ratio of the first surface stabilizer to rilpivirine is selected from 1: 0.01-1: 100, preferably 1: 1-1: 100, more preferably 1: 6-1: 60, and most preferably 1: 10-1: 30.

The weight ratio of the second surface stabilizer to rilpivirine is selected from 1: 0.01-1: 100, preferably 1: 1-1: 100, more preferably 1: 10-1: 60, and most preferably 1: 20-1: 60.

The weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 0.1:1 to 10:1, preferably 1:1 to 6:1, more preferably 1:1 to 2:1, and most preferably 2: 1.

In one embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1: 0.01-1: 100, preferably 1: 1-1: 100, more preferably 1: 6-1: 60, most preferably 1: 10-1: 30; the weight ratio of the second surface stabilizer to rilpivirine is selected from 1: 0.01-1: 100, preferably 1: 1-1: 100, more preferably 1: 10-1: 60, and most preferably 1: 20-1: 60.

In another embodiment of the present disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:0.01 to 1:100, preferably 1:1 to 1:100, more preferably 1:6 to 1:60, most preferably 1:10 to 1: 30; the weight ratio of the second surface stabilizer to rilpivirine is 1: 0.01-1: 100, preferably 1: 1-1: 100, more preferably 1: 10-1: 60, and most preferably 1: 20-1: 60; the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 0.1:1 to 10:1, preferably 1:1 to 6:1, more preferably 1:1 to 2:1, and most preferably 2: 1.

In one embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:6 to 1:60, the weight ratio of the second surface stabilizer to rilpivirine is selected from 1:10 to 1:60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 1:1 to 6: 1. In another embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:6 to 1:60, the weight ratio of the second surface stabilizer to rilpivirine is selected from 1:10 to 1:60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 1:1 to 2: 1. In another embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:6 to 1:60, the weight ratio of the second surface stabilizer to rilpivirine is selected from 1:10 to 1:60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 2: 1.

In one embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:6 to 1:60, the weight ratio of the second surface stabilizer to rilpivirine is selected from 1:20 to 1:60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 1:1 to 6: 1. In another embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:6 to 1:60, the weight ratio of the second surface stabilizer to rilpivirine is selected from 1:20 to 1:60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 1:1 to 2: 1. In another embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:6 to 1:60, the weight ratio of the second surface stabilizer to rilpivirine is selected from 1:20 to 1:60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 2: 1.

In one embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:10 to 1:30, the weight ratio of the second surface stabilizer to rilpivirine is selected from 1:10 to 1:60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 1:1 to 6: 1. In another embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:10 to 1:30, the weight ratio of the second surface stabilizer to rilpivirine is selected from 1:10 to 1:60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 1:1 to 2: 1. In another embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:10 to 1:30, the weight ratio of the second surface stabilizer to rilpivirine is selected from 1:10 to 1:60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 2: 1.

In one embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is 1: 10-1: 30, the weight ratio of the second surface stabilizer to rilpivirine is 1: 20-1: 60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is 1: 1-6: 1. In another embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:10 to 1:30, the weight ratio of the second surface stabilizer to rilpivirine is selected from 1:20 to 1:60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 1:1 to 2: 1. In another embodiment of the disclosure, the weight ratio of the first surface stabilizer to rilpivirine is selected from 1:10 to 1:30, the weight ratio of the second surface stabilizer to rilpivirine is selected from 1:20 to 1:60, and the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 2: 1.

The pharmaceutical composition disclosed by the disclosure, wherein the weight ratio of the sodium deoxycholate, the 15-hydroxystearic acid polyethylene glycol ester and the rilpivirine is 1: 1-10: 1-100, preferably 1: 1-6: 10-100, more preferably 1: 1-5: 10-80, and most preferably 1: 1-3: 20-60.

The pharmaceutical composition of the present disclosure further comprises a sedimentation inhibitor, wherein the sedimentation inhibitor includes, but is not limited to, one or more of mannitol, glucose sucrose, polyethylene glycol, dextran 40, trehalose, glycerol, povidone, glycine, hydroxypropyl- β -cyclodextrin, preferably one or more of mannitol, glucose, and polyethylene glycol, and more preferably glucose. The weight ratio of the sedimentation inhibitor to rilpivirine is 1: 0.1-1: 50, preferably 1: 0.5-1: 30, more preferably 1: 3-1: 15, and more preferably 1: 3-1: 7.

The preparation method of the pharmaceutical composition comprises the following steps: co-milling the surface stabilizer, the sedimentation inhibitor and rilpivirine to prepare the nanoparticle composition.

In the pharmaceutical composition of the present disclosure, rilpivirine is contained in an amount selected from 0.01-800mg, preferably 10-600mg, more preferably 100-600mg, and most preferably 200-600 mg.

The pharmaceutical compositions of the present disclosure also comprise a liquid medium including, but not limited to, water, saline solution, safflower seed oil, ethanol, tert-butanol, hexane and ethylene glycol, preferably water, saline solution.

In the pharmaceutical composition disclosed by the invention, the content of rilpivirine is selected from 0.01-800 mg/mL, preferably 10-600 mg/mL, more preferably 100-500 mg/mL, and most preferably 200-350 mg/mL.

The average particle size of the rilpivirine nanoparticles is less than 1000nm, preferably less than 500nm, more preferably less than 250nm, more preferably less than 220nm, more preferably less than 200nm, more preferably less than 160nm, and most preferably less than 150 nm.

The average particle size of the rilpivirine nanoparticles of the pharmaceutical compositions of the present disclosure is no greater than 500nm, preferably no greater than 300nm, more preferably no greater than 250nm, and most preferably no greater than 200nm, when stored at 2-8 ℃ for about 30 days.

The pharmaceutical compositions of the present disclosure have a D50 value for rilpivirine nanoparticles of no greater than 500nm, preferably no greater than 300nm, more preferably no greater than 250nm, and most preferably no greater than 200nm when stored at 2-8 ℃ for about 30 days.

The D90 of rilpivirine nanoparticles of the pharmaceutical compositions of the present disclosure is no greater than 600nm, preferably no greater than 500nm, more preferably no greater than 350nm, and most preferably no greater than 300nm, when stored at 2-8 ℃ for about 30 days.

In one embodiment of the present disclosure, the average particle size of the rilpivirine nanoparticles is less than 500nm, preferably less than 250nm, more preferably less than 200nm, most preferably less than 150 nm; the average particle size of rilpivirine nanoparticles is no greater than 500nm, preferably no greater than 300nm, more preferably no greater than 250nm, most preferably no greater than 200nm, when stored at 2-8 ℃ for about 30 days; a value of D50 of no more than 500nm, preferably no more than 300nm, more preferably no more than 250nm, most preferably no more than 200 nm; d90 is not higher than 600nm, preferably not higher than 500nm, more preferably not higher than 350nm, most preferably not higher than 300 nm.

In one embodiment, the pharmaceutical composition of the present disclosure may be prepared as an injection or a lyophilized formulation.

The pharmaceutical composition of the present disclosure comprises, based on the weight to volume ratio of the composition: 3-50% w/v rilpivirine, preferably 10-40% w/v rilpivirine, more preferably 20-40% w/v rilpivirine; 0.1-10% w/v of a first surface stabilizer, preferably 0.5-5% w/v of the first surface stabilizer, more preferably 0.5-3% w/v of the first surface stabilizer; 0.01% to 3% w/v of a second surface stabilizer, preferably 0.1% to 1.5% w/v of a second surface stabilizer, more preferably 0.5% to 1.5% w/v of a second surface stabilizer; 0% to 10% w/v of a sedimentation inhibitor, preferably 3% to 8% w/v of a sedimentation inhibitor, more preferably 4% to 6% w/v of a sedimentation inhibitor; from 40% to 80% w/v of liquid medium, preferably from 50% to 80% w/v of liquid medium, more preferably from 60% to 75% w/v of liquid medium.

The pharmaceutical composition of the present disclosure comprises, based on the weight to volume ratio of the composition: 3-50% w/v rilpivirine, preferably 10-40% w/v rilpivirine, more preferably 20-40% w/v rilpivirine; 0.1-10% w/v of polyethylene glycol 15-hydroxystearate, preferably 0.5-5% w/v of polyethylene glycol 15-hydroxystearate, more preferably 0.5-3% w/v of polyethylene glycol 15-hydroxystearate; 0.01-3% w/v sodium deoxycholate, preferably 0.1-1.5% w/v sodium deoxycholate, more preferably 0.5-1.5% w/v sodium deoxycholate; 0% to 10% w/v glucose, preferably 3% to 8% w/v glucose, more preferably 4% to 6% w/v glucose; from 40% to 80% w/v water, preferably from 50% to 80% w/v water, more preferably from 60% to 75% w/v water.

The preparation method of the pharmaceutical composition comprises the step of co-grinding 15-hydroxystearic acid polyethylene glycol ester, sodium deoxycholate and rilpivirine to prepare rilpivirine nanoparticle composition. Preferably, the preparation method comprises the step of co-grinding 15-hydroxystearic acid polyethylene glycol ester, sodium deoxycholate, glucose and rilpivirine in a liquid medium to prepare the rilpivirine nanoparticle composition.

In one embodiment, the milling time is generally about 15 to 1 hour, preferably 10 to 1 hour, more preferably 8 to 1 hour, more preferably 6 to 1 hour, more preferably 5 to 1 hour, and most preferably 3 to 1 hour.

In one embodiment, rilpivirine is form I having characteristic peaks in the X-ray powder diffraction pattern at 2 Θ angles of 9.0 °, 11.3 °, 14.3 °,17.1 °, 19.1 °, 24.2 ° and 27.6 °; the crystal form I is a polymorphic form I described in patent CN 101743006.

In one embodiment, rilpivirine is crystalline form II having an X-ray powder diffraction pattern with characteristic peaks at 2 Θ angles of 8.3 °, 12.2 °, 12.6 °, 17.3 °, 20.7 °, 24.5 °, 25.5 ° and 27.6 °; the crystal form II is a polymorphic form II described in patent CN 101743006.

The "2 theta or 2 theta angle" referred to in the present disclosure means the diffraction angle, theta is the bragg angle in degrees or degrees, and the error range of 2 theta is ± 0.3 or ± 0.2 or ± 0.1.

Use of a pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating HIV infection or preventing HIV infection in a subject at risk for being infected by HIV.

Use of a pharmaceutical composition described in the present disclosure for the manufacture of a medicament for the long-term treatment of an HIV infection or for the long-term prevention of an HIV infection in a subject at risk of being infected by HIV.

The medicaments of the present disclosure are for administration by intramuscular or subcutaneous injection; wherein the composition is administered intermittently at intervals of one week to two years, in one embodiment wherein the composition is administered at intervals of one week to one month, one month to three months, three months to six months, or six months to twelve months. In another embodiment, wherein the composition is administered once a week, once every two weeks, once every four weeks, once every month, or once every three months. The pharmaceutical composition disclosed by the invention has high bioavailability after subcutaneous injection, and has good safety and effectiveness.

The pharmaceutical composition of the present disclosure may also be used in combination with other HIV inhibitors, wherein the HIV inhibitors may be selected from one or more of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase preparations, protease inhibitors, or integrase inhibitors.

Nucleoside reverse transcriptase inhibitors include adefovir, azidothymidine, zalcitabine, lamivudine, emtricitabine, abacavir, fuzivudine tiate, alovudine, amdoxovir, elvucitabine, aliscitabine, and the like; non-nucleoside reverse transcriptase inhibitors include nevirapine, delavirdine, efavirenz, GSK2248761, lesivirin, etravirine, loviramine, oltipraz, carpivirine, and RDEA-806; protease inhibitors such as indinavir, ritonavir, nelfinavir, amprenavir, saquinavir, fosamprenavir, lopinavir, atazanavir, tipranavir, darunavir, bacinavir, palinavir, lacinavir; integrase inhibitors include raltegravir, eltavir, Cabotegravir.

The treatment of HIV infection described in the present disclosure relates to the treatment of subjects infected with HIV, as well as to the treatment of diseases associated with HIV infection. The prevention of HIV infection relates to preventing or avoiding infection of a subject by HIV. The treatment of HIV infection described in the present disclosure refers to a treatment whereby the viral load of HIV is reduced. The long term treatment or long term prevention of HIV infection as described in the present disclosure refers primarily to treatment or prevention of HIV infection for at least one week, two weeks, four weeks, one month, or more.

Grinding apparatuses suitable for use in the present disclosure include dispersion mills such as ball mills, attritors, vibration mills, and the like, and media mills such as sand mills and bead mills. Such dispersion mills are well known in the art.

Detailed Description

In the description and claims of the present disclosure, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present disclosure, definitions and explanations of some of the relevant terms are provided below.

The solvent used in the co-milling in the present disclosure may be a liquid medium; the aqueous carrier in the injection solution may be a liquid medium, which is the same as that described above.

The saline solution described in the present disclosure includes, but is not limited to, physiological saline solution, buffered saline solution (including, but not limited to, ammonia-ammonium chloride buffer, citrate buffer, acetic acid-sodium acetate buffer, phosphate buffer).

The subject of the present disclosure is particularly a human.

As used herein, the "weight to volume ratio" (w/v) refers to the weight (in g) of the component per 100mL of liquid system, i.e., g/100 mL. When the substances in the pharmaceutical composition of the present disclosure are expressed by weight to volume ratio, the pharmaceutical composition further comprises a liquid medium, and the liquid medium is the same as the liquid medium described above.

As used herein, "D10" refers to the particle size corresponding to a cumulative percent particle size distribution of 10% for a sample. "D50" refers to the particle size corresponding to the cumulative percent particle size distribution of a sample at 50%. "D90" refers to the particle size corresponding to 90% of the cumulative percent particle size distribution for a sample.

The "average particle Size" (Z-average Size), e.g. "average particle Size less than 2000 nm", as used herein is the average of the intensities of light, as calculated from the intensities of light contributed by the different types of particles. The "average particle size" may be measured by conventional particle size measurement techniques well known to those skilled in the art. Such techniques include, for example, sedimentation field flow fractionation, photon correlation spectroscopy, light scattering, and the like.

The Polydispersity Index "PDI" (Polydispersity Index) of the present disclosure represents the degree of particle size uniformity, and is an important Index for particle size characterization.

The content (including percentage content) and the ratio of each substance in the composition are allowed to have a tolerance of +/-5%, for example, the fact that the content of rilpivirine in the composition is selected from 200-350 mg/mL means that the content of rilpivirine nanoparticles in the composition is 195-355 mg/mL, which belongs to the scope of the disclosure; "comprising 30% rilpivirine nanoparticles" means that it is within the scope of the disclosure to comprise 25-35% rilpivirine nanoparticles; the weight ratio of the sedimentation inhibitor to the rilpivirine nanoparticles is selected from 1: 3-1: 6, which means that the weight ratio of the sedimentation inhibitor to the rilpivirine nanoparticles is selected from 1: 2.5-1: 6.5 are within the scope of the present disclosure. In the present disclosure, "about" means a regimen that includes an error of ± 5%.

The terms "mixing" and "mixing" in the present disclosure mean not to limit the order of addition of the components, and for example, mixing a into B may mean adding a into B, or may mean adding B into a, or mixing a and B may mean adding a into B, or may mean adding B into a.

Advantageous effects of the invention

The present disclosure improves the dispersibility of nanoparticles in suspensions by adding a surface stabilizer to injectable pharmaceutical compositions comprising rilpivirine nanoparticles. The sedimentation or aggregation of the nanoparticles can be inhibited by adding a sedimentation inhibitor such as mannitol and anhydrous glucose into the composition. In some embodiments of the present disclosure, a nonionic surfactant, an anionic surfactant, a sedimentation inhibitor, etc. are selected to prepare rilpivirine nanoparticles together, the average particle size of the rilpivirine nanoparticles after grinding is less than 300nm, the average particle size does not increase significantly after storage for 30 days at 2-8 ℃, and the preparation is stable.

Detailed Description

The present disclosure is further illustrated in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

The particle size of the nanoparticle injection in the following examples is measured by the third method of 0982, the fourth general rule of pharmacopoeia 2015 edition of china.

Malvern Nano-particle size potentiometer Zetasizer Nano ZS, dispersion medium: purifying the water; dilution times are as follows: diluting to rilpivirine concentration of about 0.06 mg/ml; and (3) testing temperature: 25 ℃; absorption rate: 0.01; a refractive index of 1.66; the balance time is as follows: 120 s; test position: the optimal position.

The average particle size described in the examples refers to the average particle size measured with a malvern Nano-particle size potentiometer Zetasizer Nano ZS.

Malvern laser sizer Mastersizer 2000, dispersion medium: purifying the water; sensitivity: normal; refractive index: 1.665; absorption rate: 0.01; background measurement time: 12 s; sample measurement time: 12 s; stirring speed: 1500 rpm; light-shielding degree range: 5 to 10 percent.

Polyethylene glycol 15-hydroxystearate (also known as polyethylene glycol-12-hydroxystearate, abbreviated as HS 15) with trade name

(Basff, Germany).

EXAMPLE 1 preparation of Ripivirine starting Material

Rilpivirine free base was prepared according to CN100509801C specification example B1.

Example 2 prescription 1-rilpivirine, Poloxamer formulation

TABLE 1 formulation of rilpivirine and poloxamer

The preparation method comprises the following steps: dissolving a prescribed amount of poloxamer, anhydrous glucose, and about half of the total weight in water; adding the rilpivirine raw material with the prescription amount into the solution, adding water for injection to a target volume, and stirring and mixing uniformly by using a glass rod; the mixed solution was put into a grinding pot filled with grinding beads, stirred uniformly, and ground in a ball mill, and the grinding results are shown in table 2.

TABLE 2 grinding particle size results

The experimental results show that the average particle size can only be reduced to about 250 nm.

EXAMPLE 3 prescription of 2-rilpivirine, Tween 20 preparation

TABLE 3 formulation of rilpivirine and Tween 20

Specific procedures particle size was measured using malvern 2000 with reference to example 2, and the grinding results are shown in table 4 below.

TABLE 4 grinding particle size results

When the particle size is detected and sampled, the viscosity of the liquid medicine is higher, the sampling is difficult, the grinding is stopped, and the particle size distribution is wider.

Example 4 formulation of 3-rilpivirine, Povidone K17

TABLE 5 formulation of rilpivirine, povidone K17

The specific procedure is as in example 2, taking 0.1ml of the detected particle size, the grinding results are shown in Table 6 below.

TABLE 6 grinding particle size results

The particle size detection result shows that the particle size is larger and the distribution is wider.

Example 5 formulation of rilpivirine, polyethylene glycol 15-hydroxystearate

TABLE 7 formulation screening of rilpivirine and polyethylene glycol 15-hydroxystearate

The above proportions are weight to volume ratios.

The preparation method comprises the following steps: dissolving a prescribed amount of a stabilizer and a settling inhibitor in about half of the total weight of water; adding the rilpivirine raw material with the prescription amount into the solution, adding water for injection to a target volume, and stirring and mixing uniformly by using a glass rod; adding the mixed solution into a grinding tank filled with grinding beads, stirring, taking 0.1ml to detect the particle size, and the grinding results are shown in Table 8 below

TABLE 8 grinding particle size results

From the data in table 8, it can be seen that the formulation of formula 4 does not allow the particle size to be reduced below 300 nm; formula 5 has low grinding efficiency, small particle size reduction range and wide particle size distribution; the average particle diameter of the rest formulas can be less than 250 nm.

TABLE 9 formulation of rilpivirine, polyethylene glycol 15-hydroxystearate, glucose

The above proportions are weight to volume ratios.

The preparation method comprises the following steps: dissolving a prescribed amount of a stabilizer and a settling inhibitor in about half of the total weight of water; adding the rilpivirine raw material with the prescription amount into the solution, adding water for injection to a target volume, and stirring and mixing uniformly by using a glass rod; the mixed solution was put into a grinding pot filled with grinding beads and stirred uniformly, and 0.1ml of the mixed solution was taken out to measure the particle size, and the grinding results are shown in the following table 10.

TABLE 10 results of grinding particle size

As can be seen from the data in Table 10, the average particle size was less than 300nm and the PDI was below 0.5 for all formulations 9-15 after milling, the particle size and distribution results for the drug were good.

Example 6 stability Studies of Ripivirine formulation formulations

The nanosuspensions obtained by the formulas 7-10 and 15 were placed at 2-8 ℃ under the condition of humidity replenishment, and the particle size distribution was examined for about 0-30 days, as shown in table 11.

TABLE 11 particle size stability data for recipe 6, recipe 7, recipe 8, recipe 9, and recipe 10

As can be seen from the data in table 11, the rilpivirine nanoparticle injection is stable under the above conditions, and the particle size distribution is not significantly changed from the initial one.

Claims

1. A pharmaceutical composition comprising rilpivirine nanoparticles and a surface stabilizer, wherein the surface stabilizer comprises a first surface stabilizer polyethylene glycol stearate or a derivative thereof and a second surface stabilizer selected from one or more of sodium deoxycholate, sodium cholate, sodium hydroxymethylcellulose, sodium docusate, preferably one or more of sodium deoxycholate, sodium hydroxymethylcellulose, more preferably sodium deoxycholate.

2. The pharmaceutical composition according to claim 1, wherein the polyethylene glycol stearate or derivative thereof is selected from 15-hydroxypolyethylene glycol stearate, and the second surface stabilizer is selected from sodium deoxycholate, sodium cholate, sodium hydroxymethylcellulose, sodium docusate, preferably one or more of sodium deoxycholate and sodium hydroxymethylcellulose, more preferably sodium deoxycholate.

3. The pharmaceutical composition according to claim 2, wherein the weight ratio of the first surface stabilizer to rilpivirine is selected from 1: 0.01-1: 100, preferably 1: 1-1: 100, more preferably 1: 6-1: 60, most preferably 1: 10-1: 30.

4. The pharmaceutical composition according to claim 2, wherein the weight ratio of the secondary surface stabilizer to rilpivirine is selected from 1: 0.01-1: 100, preferably 1: 1-1: 100, more preferably 1: 10-1: 60, most preferably 1: 20-1: 60.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the weight ratio of the first surface stabilizer to the second surface stabilizer is selected from 0.1:1 to 10:1, preferably 1:1 to 6:1, more preferably 1:1 to 2:1, most preferably 2: 1.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the weight ratio of surface stabilizer to rilpivirine is selected from 1:0.01 to 1:100, preferably 1:1 to 1:80, more preferably 1:5 to 1:30, most preferably 1:6.5 to 1: 20.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the weight ratio of sodium deoxycholate, 15-hydroxystearic acid polyethylene glycol ester and rilpivirine is 1: 1-10: 1-100, preferably 1: 1-6: 10-100, more preferably 1: 1-5: 10-80, and most preferably 1: 1-3: 20-60.

8. The pharmaceutical composition according to any one of claims 1-7, wherein said pharmaceutical composition further comprises a sedimentation inhibitor.

9. The pharmaceutical composition according to claim 8, wherein the sedimentation inhibitor is selected from one or more of mannitol, glucose, sucrose, polyethylene glycol, dextran 40, trehalose, glycerol, povidone, glycine, hydroxypropyl- β -cyclodextrin, preferably one or more of mannitol, glucose, polyethylene glycol, more preferably glucose.

10. The pharmaceutical composition of claim 9, wherein the weight ratio of the sedimentation inhibitor to rilpivirine is selected from 1:0.1 to 1:50, preferably 1:0.5 to 1:30, more preferably 1:3 to 1:15, most preferably 1:3 to 1: 7.

11. The pharmaceutical composition according to any one of claims 1-10, wherein the pharmaceutical composition comprises rilpivirine in an amount selected from the group consisting of 0.01-800mg, preferably 10-600mg, more preferably 100-600mg, most preferably 200-600 mg.

12. The pharmaceutical composition according to claims 1-11, wherein the pharmaceutical composition further comprises a liquid medium selected from one or more of water, saline solution, preferably water.

13. The pharmaceutical composition according to claim 12, wherein the content of rilpivirine in the pharmaceutical composition is selected from 0.01-800 mg/mL, preferably 10-600 mg/mL, more preferably 100-500 mg/mL, most preferably 200-350 mg/mL.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the rilpivirine nanoparticles have an average particle size of less than 500nm, preferably less than 250nm, more preferably less than 200nm, most preferably less than 150 nm.

15. The pharmaceutical composition of claim 14, wherein the average particle size of rilpivirine nanoparticles is no greater than 500nm, preferably no greater than 300nm, more preferably no greater than 250nm, most preferably no greater than 200nm, when the pharmaceutical composition is stored at 2-8 ℃ for about 30 days.

16. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition has a D50 value for rilpivirine nanoparticles of no greater than 500nm, preferably no greater than 300nm, more preferably no greater than 250nm, most preferably no greater than 200nm, when stored at 2-8 ℃ for about 30 days.

17. The pharmaceutical composition of claim 14, wherein the D90 of rilpivirine nanoparticles is no greater than 600nm, preferably no greater than 500nm, more preferably no greater than 350nm, most preferably no greater than 300nm, when the pharmaceutical composition is stored at 2-8 ℃ for about 30 days.

18. The pharmaceutical composition of any one of claims 1-17, wherein the pharmaceutical composition is prepared as an injection solution or a lyophilized formulation.

19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition comprises, based on the weight to volume ratio of the composition:

a) 3-50% w/v rilpivirine, preferably 10-40% w/v rilpivirine, more preferably 20-40% w/v rilpivirine;

b) 0.1-10% w/v of polyethylene glycol 15-hydroxystearate, preferably 0.5-5% w/v of polyethylene glycol 15-hydroxystearate, more preferably 0.5-3% w/v of polyethylene glycol 15-hydroxystearate;

c) 0.01-3% w/v sodium deoxycholate, preferably 0.1-1.5% w/v sodium deoxycholate, more preferably 0.5-1.5% w/v sodium deoxycholate;

d) 0% to 10% w/v glucose, preferably 3% to 8% w/v glucose, more preferably 4% to 6% w/v glucose;

e) from 40% to 80% w/v water, preferably from 50% to 80% w/v water, more preferably from 60% to 75% w/v water.

20. A process for preparing a pharmaceutical composition according to any one of claims 1 to 19, comprising: co-milling the surface stabilizer with rilpivirine to prepare the nanoparticle composition.

21. A method of preparing the pharmaceutical composition of claim 20, comprising: co-milling the surface stabilizer, the sedimentation inhibitor and rilpivirine to prepare the nanoparticle composition.

22. Use of a pharmaceutical composition according to any one of claims 1-19 for the manufacture of a medicament for treating HIV infection or preventing HIV infection in a subject at risk of being infected by HIV.

23. The use according to claim 22, wherein the pharmaceutical composition is used in combination with other HIV inhibitors, wherein the HIV inhibitors may be selected from one or more of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase preparations, protease inhibitors or integrase inhibitors.