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CN-121971388-A - Long-acting injection of lyotropic liquid crystal, its preparation method and application

CN121971388ACN 121971388 ACN121971388 ACN 121971388ACN-121971388-A

Abstract

The invention discloses a long-acting lyotropic liquid crystal injection, a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The preparation consists of bulk drugs, lipid materials, organic solvents and release regulators, and can spontaneously form hexagonal phase liquid crystal gel after injection so as to realize long-acting slow release. The preparation is prepared by stirring and mixing at room temperature, and has the advantage of simple preparation process. Experiments show that the effective blood concentration in the body can be maintained for more than 14 days after single subcutaneous injection, the half life of the medicine is prolonged from about 66 hours to 187 hours at most after oral administration, and no burst release phenomenon exists. The invention effectively solves the clinical pain points of frequent administration, large fluctuation of blood concentration, poor patient compliance and the like of the existing oral preparation of the voathitine hydrobromide.

Inventors

  • WANG SILING
  • HE YE
  • ZHOU MENGYUE
  • ZHAO QINFU
  • ZHANG WEI

Assignees

  • 沈阳药科大学

Dates

Publication Date
20260505
Application Date
20260204

Claims (9)

  1. 1. A long-acting injection of lyotropic liquid crystal is characterized by comprising the following components of bulk drugs, lipid materials and organic solvents; the bulk drug is vomeropherin or pharmaceutically acceptable salt thereof; The lipid material consists of phospholipid and grease; the organic solvent is one or more selected from ethanol, N-methyl pyrrolidone, glycerol, propylene glycol, benzyl alcohol, glycerol formal and polyethylene glycol 400.
  2. 2. The long-acting injection of lyotropic liquid crystal according to claim 1, wherein the long-acting injection component further comprises a release regulator, and the release regulator is one or more selected from cholesterol, stearic acid, nonadecanoic acid, D-alpha-tocopherol, ethyl linoleate, triglycerin monostearate, polylactic acid-glycolic acid copolymer, pluronic P188, pluronic P407 and polyethylene glycol 2000.
  3. 3. The lyotropic liquid crystal long-acting injection of claim 1, wherein the pharmaceutically acceptable salts of the vomeropherin include hydrobromide, hydrochloride, sulfate and citrate thereof.
  4. 4. The long-acting injection for lyotropic liquid crystals according to claim 1, wherein the phospholipid is one or more selected from egg yolk lecithin, soybean lecithin, hydrogenated lecithin, distearoyl phosphatidylcholine and dioleoyl phosphatidylcholine, and the oil is one or more selected from glycerol monooleate, glycerol monostearate, glycerol dioleate, glycerol trioleate, glycerol monolinoleate, glycerol trilinoleate and glycerol monolinoleate.
  5. 5. The lyotropic liquid crystal long-acting injection according to claim 1, wherein the mass ratio of the phospholipid to the oil is 9:1 to 1:9.
  6. 6. The lyotropic liquid crystal long-acting injection according to claim 2, wherein the weight percentages of the components are as follows, based on the total mass of the injection: the weight percentage of the raw material medicines is 5% -20%; the weight percentage of the lipid material is 15% -90%; The weight percentage of the organic solvent is 5% -50%; the weight percentage of the release regulator is 1% -30%.
  7. 7. The long-acting lyotropic liquid crystal injection as claimed in claim 6, wherein the weight percentages of the components are as follows, based on the total mass of the injection: the weight percentage of the raw material medicines is 8% -15%; the weight percentage of the organic solvent is 15% -40%; the weight percentage of the release regulator is 4% -20%.
  8. 8. A method for preparing the lyotropic liquid crystal long-acting injection according to any of claims 1 to 7, which is characterized by comprising the steps of stirring and mixing phospholipid, grease and an organic solvent at room temperature to form a uniform solution, adding the vomeropherin or pharmaceutically acceptable salt thereof into the uniform solution, continuously stirring until the vomeropherin or pharmaceutically acceptable salt thereof is completely dissolved, filtering the obtained drug-loaded precursor solution through a 0.22 mu m filter membrane, filling nitrogen, and stirring the drug-loaded precursor solution with the phospholipid, the grease and the organic solvent at room temperature if a release regulator is also contained in a formulation prescription.
  9. 9. Use of a long-acting injection of lyotropic liquid crystals as claimed in any of claims 1 to 7 in the manufacture of a long-acting drug delivery formulation for the treatment of depression, characterized in that the injection forms a hexagonal phase lyotropic liquid crystal gel after subcutaneous injection and the cumulative release of drug over 24 hours is less than 6% and the sustained release time is over 14 days.

Description

Long-acting injection of lyotropic liquid crystal, its preparation method and application Technical Field The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a long-acting injection of a voethidine lyotropic liquid crystal, a preparation method and application thereof. Background Depression is currently the fourth world-wide disease. World health organization 2023 counts that about 2.8 million people worldwide are suffering from depression, the number of people suffering from depression in China is 9500 ten thousand, wherein the lifetime prevalence rate of adult depression disorder is 6.8%, and the number of depression patients under 18 years in the incidence group is 30% of the total number, more than 72 ten thousand people die from suicide each year. Treatment of depression currently advocates full course therapy with recurrence rates up to 72% and should be maintained for at least 2-3 years in patients with a predisposition to recurrence. Compared with selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRIs) and the like, the novel antidepressant with a brand new multimode action mechanism has better clinical research results in the aspects of improving cognitive symptoms such as executive functions, learning, memory, information processing speed, attention and the like in multiple dimensions, and has good safety and tolerance. According to the instructions of depression basic diagnosis and treatment (practice edition 2021) and the instructions of expert recommendation of depression treatment and management (2022 years), depression drug treatment generally starts from 2-4 weeks, the effective rate of treatment is in a linear relation with time, and patients use enough drugs for treatment for 4-6 weeks, if not, the drugs with the same kind of other drugs or different action mechanisms are replaced. Meanwhile, the tablet specifications of the variety on the market also write that after depression symptoms are relieved, the variety is recommended to be continuously treated for at least 6 months so as to consolidate the anti-depression curative effect. Thus, the treatment period with the medicine is long, and at least 1 month is needed. Patients taking medicines for a long time insist on taking medicines every day, take the medicines well and have accurate dosages, which is a difficult thing and can cause great mental burden to the patients. Therefore, development of a long-acting preparation of the hydrobromic acid volt-sulfur sitagliptin is imperative. The existing commercial preparation of the voethidine hydrobromide has only one oral tablet, needs to be taken every day, and has poor patient compliance. In addition, the oral preparation has the problems of bitter taste, gastrointestinal irritation (such as nausea and diarrhea), large fluctuation of blood concentration and the like, and especially the safety of the elderly patients and the patients with liver and kidney insufficiency needs to be further optimized. Other related preparations of the voethionamide hydrobromide currently include dripping pills, orally disintegrating tablets, injections, tablets and the like by referring to related literature patents. Wherein, except one long-acting suspension agent disclosed in the prior art, the slow release effect can be realized for more than 1 day, and the rest of the action time is less than 1 day. The drug suspension has remarkable advantages in the aspects of onset speed and bioavailability, is used as a thermodynamically unstable heterogeneous system, has stability inferior to that of a common oral preparation, and contains solid drug particles which possibly trigger pain response at the administration position in clinical application. The hydrobromic acid votiazem has high solubility in organic solvents such as methanol, ethanol and the like, is slightly dissolved in water, and is a fat-soluble compound with high affinity to peripheral tissues. The lyotropic liquid crystal precursor oil solution mainly comprises glycerol monooleate (glyceryl monooleate, GMO), glycerol dioleate (glycerol dioleate, GDO), phospholipid amphiphilic molecules, ethanol, N-methylpyrrolidone (NMP) and other hydrophilic solvents. According to similar compatibility, the liquid crystal precursor solution has better solubility for the hydrobromic acid voathixetine, and can realize larger drug loading. After the amphiphilic molecules in the precursor oil solution are contacted with body fluid, the polar head and the hydrophobic tail of the amphiphilic molecules interact with water molecules to form lamellar, spherical or cylindrical micelles by self-assembly, and finally lamellar, bicontinuous cubic phase, hexagonal intermediate phase or micelle cubic phase lyotropic liquid crystal gel is formed. The liquid crystal gel has proper viscoelasticity, thermodynamic stability and ordered internal nano structure as medicin