CN112891307A - Liquid pharmaceutical formulation of lamivudine - Google Patents

Liquid pharmaceutical formulation of lamivudine Download PDF

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CN112891307A
CN112891307A CN202110120405.9A CN202110120405A CN112891307A CN 112891307 A CN112891307 A CN 112891307A CN 202110120405 A CN202110120405 A CN 202110120405A CN 112891307 A CN112891307 A CN 112891307A
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lamivudine
acid
liquid
ionic liquid
cyclodextrin
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孟祥龙
宋艳丽
代素霞
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Jiaxing Juetuo Technology Co ltd
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Abstract

The invention provides a liquid pharmaceutical preparation of lamivudine, which comprises the following components: an effective amount of micronized lamivudine or a pharmaceutically acceptable salt thereof; an ionic liquid; an absorption enhancer; water; and optionally the following ingredients: acid-base regulator, osmotic pressure regulator, thickener and antiseptic; the ionic liquid is alkyl imidazole ionic liquid and has a structure shown as a formula I, wherein R is1，R2H, C1-C5 alkyl. The invention adopts ionic liquid to dissolve the sodium alginateThe solubility of the medicinal active ingredients is increased, and the biomembrane passing property of the medicinal active ingredients is improved, so that the bioavailability of the lamivudine is improved, the drug effect is accelerated, the dosage form of the liquid pharmaceutical composition is not influenced, the quality guarantee period is long, the liquid drug delivery can be realized, the liquid pharmaceutical composition is suitable for dysphagia patients, and the application prospect is wide.
Figure DDA0002921834930000011

Description

Liquid pharmaceutical formulation of lamivudine
Technical Field
The invention relates to the technical field of biological pharmacy, in particular to a liquid pharmaceutical preparation of lamivudine.
Background
Lamivudine (Lamivudine) is a deoxycytidine nucleoside analogue with the chemical name (2R,5S) -4-amino-1- (2-hydroxymethyl-1, 3-oxathiolan-5-yl) - (1H) -pyrimidin-2-one, formula: c8H11N3O3S, the chemical structural formula is as follows:
Figure BDA0002921834910000011
lamivudine is a nucleoside antiviral drug developed by Kuran-Scker company, and has strong inhibitory effect on Hepatitis B Virus (HBV) in vitro and in experimental infected animals. The results of serum HBV DNA tests on most hepatitis B patients show that lamivudine can rapidly inhibit HBV replication, and the inhibition effect lasts for the whole treatment process, and simultaneously serum aminotransferase is reduced to normal. Long-term use can significantly ameliorate the inflammatory changes of liver necrosis and reduce or prevent the progression of liver fibrosis. Nucleotides are the raw material for the synthesis of human genetic material DNA and RNA. The nucleoside analogue structurally simulates the structure of nucleotide, and the lamivudine simulates the cytosine of the hepatitis B virus, has a structure different from the structure of natural human cytosine, can act on the virus, and reduces side effects on a human body.
Lamivudine has poor solubility, tablet dissolution is slow, and the tablet is easy to absorb moisture, so that the hardness of the tablet is reduced, moisture absorption spots are generated on the surface, and the curative effect, namely the stability of the tablet is poor.
It is well known to those skilled in the art that the absorption rate of a drug in the body is often determined by the rate of dissolution, the drug in a solid preparation must undergo disintegration and dissolution before being absorbed and then turn into a solution, if the drug is not easily released from the preparation or the dissolution rate of the drug is very slow, the absorption rate or extent of the drug in the preparation is affected, most oral solid preparations must be absorbed into the blood circulation after administration to achieve a certain blood concentration before they can be effective, and thus the drug is released from the preparation and dissolved in the body fluid is a prerequisite for absorption. The dissolution test is used as an effective alternative method for researching and evaluating the bioavailability of the in-vivo drug in vitro, can indirectly reflect the dissolution and absorption process in vivo, and the drug with low initial dissolution rate needs longer time to reach the steady blood concentration in vivo, and correspondingly prolongs the time of exerting the drug effect, thereby influencing the treatment effect of the drug.
Disclosure of Invention
The invention aims to provide a liquid pharmaceutical preparation of lamivudine, which is dissolved by adopting ionic liquid, so that the solubility of medicinal active ingredients is increased, and the biomembrane passing performance of the medicinal active ingredients is improved, thereby improving the bioavailability of lamivudine and accelerating the exertion of the drug effect.
The technical scheme of the invention is realized as follows:
the invention provides a liquid pharmaceutical preparation of lamivudine, which comprises the following components:
an effective amount of micronized lamivudine or a pharmaceutically acceptable salt thereof;
an ionic liquid;
an absorption enhancer;
water;
and optionally the following ingredients: acid-base regulator, osmotic pressure regulator, thickener and antiseptic;
the ionic liquid is an alkyl imidazole ionic liquid and has a structure shown in a formula I:
Figure BDA0002921834910000021
wherein R is1，R2H, C1-C5 alkyl.
As a further improvement of the invention, the absorption enhancer is one or a mixture of several selected from methyl-beta-cyclodextrin, dimethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfomethyl ether-beta-cyclodextrin, maltosyl-beta-cyclodextrin and lauryl nitrogen.
As a further improvement of the invention, the lamivudine or the pharmaceutically acceptable salt thereof comprises a salt of lamivudine with an organic acid or an inorganic acid.
As a further improvement of the present invention, the lamivudine or a pharmaceutically acceptable salt thereof includes a salt of lamivudine with citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid or nitric acid.
As a further improvement of the invention, the acid-base regulator is selected from one or a mixture of more of citric acid, lactic acid, malic acid, fumaric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, sodium hydroxide and potassium hydroxide; the preservative is selected from one or more of methyl paraben, ethyl paraben, propyl paraben, butyl paraben, sodium benzoate, benzyl alcohol and chlorobutanol; the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, boric acid and borax; the thickening agent is one or a mixture of more of carbomer, cross-linked sodium polyacrylate, poloxamer, polyvinyl alcohol, sodium alginate, glycerol and propylene glycol.
As a further improvement of the invention, the liquid medicine composition contains 0.1-20 wt% of lamivudine or pharmaceutically acceptable salts thereof.
As a further development of the invention, the one dose of the pharmaceutical liquid composition is in the range of 1ml to 10 ml.
As a further improvement of the invention, the formula is as follows:
formula 1: 300mg of micronized lamivudine, 0.5g of lactic acid, 0.5g of laurocapram, 1.0g of sodium alginate, 0.1g of ethylparaben, 5g of glucose, 7g of ionic liquid and 100g of water; the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the ionic liquid, adding lactic acid, glucose, laurocapram, sodium alginate and ethylparaben into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain a liquid composition; or the like, or, alternatively,
and (2) formula: 500mg of micronized lamivudine, 2.5g of maltosyl-beta-cyclodextrin, 0.1g of methyl paraben, 2g of glycerol, 1.2g of malic acid, 0.9g of sodium chloride, 10g of ionic liquid and 100g of water; the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the ionic liquid, adding malic acid, sodium chloride, maltosyl-beta-cyclodextrin, glycerol and methyl paraben into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain a liquid composition; or the like, or, alternatively,
and (3) formula: 900mg of micronized lamivudine, 2.5g of maltosyl-beta-cyclodextrin, 0.1g of sodium benzoate, 2g of carbomer, 1.9g of fumaric acid, 0.1g of sodium hydroxide, 0.9g of sodium chloride, 10g of ionic liquid and 100g of water; the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the amount into ionic liquid, adding fumaric acid, sodium hydroxide, sodium chloride, dimethyl-beta-cyclodextrin, carbomer and sodium benzoate into a proper amount of distilled water, fully stirring and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain a liquid composition, thus obtaining the liquid composition.
As a further improvement of the invention, it is in a dosage form for nasal administration.
As a further improvement of the invention, the medicine is a nasal spray or a nasal drop.
The invention has the following beneficial effects: because the solubility of the lamivudine is poor, the ionic liquid is adopted to dissolve the lamivudine, the solubility of the medicinal active ingredient is increased, and the biomembrane passing property of the medicinal active ingredient is improved, so that the bioavailability of the lamivudine is improved, the drug effect is accelerated, the alkylated imidazole ionic liquid is adopted, has excellent hydrophilicity and can be mutually dissolved with water, the dosage form of the liquid drug composition is not influenced, and the prepared liquid drug composition has better compatibility and stability, has long shelf life, can be administered in liquid, is suitable for patients with dysphagia and has wide application prospect;
according to the invention, the selection of the spray pump and the dosing pump: the dosage forms for nasal administration include nasal drops, aerosols, sprays, gels, microspheres, microparticles and nanoparticles, liposomes and emulsions. According to the convenience of clinical medication, the feasibility of industrial production and the comprehensive analysis of the characteristics of the preparation formulation, the spray and the nasal drops are preferred in the invention. Preferred compositions of the invention have good drug absorption characteristics.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a structural diagram of Compound 1 in test example 2 of the present invention;
FIG. 2 is a structural diagram of Compound 2 in test example 2 of the present invention;
FIG. 3 is a graph of mean plasma concentration versus time for test example 3 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The ionic liquids of examples 1-10 were all available from Reynolds Biotechnology, Inc., Guangzhou.
Example 1
The raw materials comprise: 300mg of micronized lamivudine, 0.5g of lactic acid, 0.5g of laurocapram, 1.0g of sodium alginate, 0.1g of ethylparaben, 5g of glucose, 7g of ionic liquid and 100g of water;
the structural formula of the ionic liquid is as follows:
Figure BDA0002921834910000041
the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the ionic liquid, adding lactic acid, glucose, laurocapram, sodium alginate and ethylparaben into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain the liquid composition.
Example 2
The raw materials comprise: 300mg of micronized lamivudine, 0.5g of lactic acid, 0.5g of laurocapram, 1.0g of sodium alginate, 0.1g of ethylparaben, 5g of glucose, 7g of ionic liquid and 100g of water;
the structural formula of the ionic liquid is as follows:
Figure BDA0002921834910000042
the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the ionic liquid, adding lactic acid, glucose, laurocapram, sodium alginate and ethylparaben into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain the liquid composition.
Example 3
The raw materials comprise: 300mg of micronized lamivudine, 0.5g of lactic acid, 0.5g of laurocapram, 1.0g of sodium alginate, 0.1g of ethylparaben, 5g of glucose, 7g of ionic liquid and 100g of water;
the structural formula of the ionic liquid is as follows:
Figure BDA0002921834910000051
the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the ionic liquid, adding lactic acid, glucose, laurocapram, sodium alginate and ethylparaben into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain the liquid composition.
Example 4
The raw materials comprise: 300mg of micronized lamivudine, 0.5g of lactic acid, 0.5g of laurocapram, 1.0g of sodium alginate, 0.1g of ethylparaben, 5g of glucose, 7g of ionic liquid and 100g of water;
the structural formula of the ionic liquid is as follows:
Figure BDA0002921834910000052
the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the ionic liquid, adding lactic acid, glucose, laurocapram, sodium alginate and ethylparaben into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain the liquid composition.
Example 5
The raw materials comprise: 300mg of micronized lamivudine, 0.5g of lactic acid, 0.5g of laurocapram, 1.0g of sodium alginate, 0.1g of ethylparaben, 5g of glucose, 7g of ionic liquid and 100g of water;
the structural formula of the ionic liquid is as follows:
Figure BDA0002921834910000053
the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the ionic liquid, adding lactic acid, glucose, laurocapram, sodium alginate and ethylparaben into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain the liquid composition.
Example 6
The raw materials comprise: 500mg of micronized lamivudine, 2.5g of maltosyl-beta-cyclodextrin, 0.1g of methyl paraben, 2g of glycerol, 1.2g of malic acid, 0.9g of sodium chloride, 10g of ionic liquid and 100g of water;
the structural formula of the ionic liquid is as follows:
Figure BDA0002921834910000061
the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the ionic liquid, adding malic acid, sodium chloride, maltosyl-beta-cyclodextrin, glycerol and methyl paraben into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain the liquid composition.
Example 7
The raw materials comprise: 500mg of micronized lamivudine, 2.5g of maltosyl-beta-cyclodextrin, 0.1g of methyl paraben, 2g of glycerol, 1.2g of malic acid, 0.9g of sodium chloride, 10g of ionic liquid and 100g of water;
the structural formula of the ionic liquid is as follows:
Figure BDA0002921834910000062
the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the ionic liquid, adding malic acid, sodium chloride, maltosyl-beta-cyclodextrin, glycerol and methyl paraben into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain the liquid composition.
Example 8
The raw materials comprise: 900mg of micronized lamivudine, 2.5g of maltosyl-beta-cyclodextrin, 0.1g of sodium benzoate, 2g of carbomer, 1.9g of fumaric acid, 0.1g of sodium hydroxide, 0.9g of sodium chloride, 10g of ionic liquid and 100g of water;
the structural formula of the ionic liquid is as follows:
Figure BDA0002921834910000063
the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the amount into ionic liquid, adding fumaric acid, sodium hydroxide, sodium chloride, dimethyl-beta-cyclodextrin, carbomer and sodium benzoate into a proper amount of distilled water, fully stirring and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain a liquid composition, thus obtaining the liquid composition.
Example 9
The raw materials comprise: 900mg of micronized lamivudine, 2.5g of maltosyl-beta-cyclodextrin, 0.1g of sodium benzoate, 2g of carbomer, 1.9g of fumaric acid, 0.1g of sodium hydroxide, 0.9g of sodium chloride, 10g of ionic liquid and 100g of water;
the structural formula of the ionic liquid is as follows:
Figure BDA0002921834910000064
the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the amount into ionic liquid, adding fumaric acid, sodium hydroxide, sodium chloride, dimethyl-beta-cyclodextrin, carbomer and sodium benzoate into a proper amount of distilled water, fully stirring and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain a liquid composition, thus obtaining the liquid composition.
Example 10
The raw materials comprise: 900mg of micronized lamivudine, 2.5g of maltosyl-beta-cyclodextrin, 0.1g of sodium benzoate, 2g of carbomer, 1.9g of fumaric acid, 0.1g of sodium hydroxide, 0.9g of sodium chloride, 10g of ionic liquid and 100g of water;
the structural formula of the ionic liquid is as follows:
Figure BDA0002921834910000071
the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the amount into ionic liquid, adding fumaric acid, sodium hydroxide, sodium chloride, dimethyl-beta-cyclodextrin, carbomer and sodium benzoate into a proper amount of distilled water, fully stirring and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain a liquid composition, thus obtaining the liquid composition.
Comparative example 1
Compared with example 10, the ionic liquid replaces deionized water.
The raw materials comprise: 900mg of micronized lamivudine, 2.5g of maltosyl-beta-cyclodextrin, 0.1g of sodium benzoate, 2g of carbomer, 1.9g of fumaric acid, 0.1g of sodium hydroxide, 0.9g of sodium chloride, 10g of deionized water and 100g of water;
the preparation method of the composition of the formula comprises the following steps: adding the micronized lamivudine into deionized water, adding fumaric acid, sodium hydroxide, sodium chloride, dimethyl-beta-cyclodextrin, carbomer and sodium benzoate into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain a liquid composition, wherein the liquid composition is a suspension and is not completely dissolved.
Test example 1
The liquid compositions obtained in examples 1 to 10 of the present invention and comparative example 1 were added to each of polyoxyethylene hydrogenated castor oil, polyethylene sorbitan monooleate, polyoxyethylene octyldodecyl ether, polysorbate 20, polysorbate 60 and polysorbate 80 as solubilizing agents at 5.0 wt% with respect to the total liquid weight to prepare liquid compositions. The liquid composition was left at room temperature conditions (25 ℃, 60%) to check whether precipitation occurred, and the time point (days) when precipitation occurred at 5.0 vol% on the bottom of the sample container was measured. The results are shown in table 1 below.
TABLE 1
Figure BDA0002921834910000072
Figure BDA0002921834910000081
As can be seen in table 1, it was confirmed that 5.0 vol% or more of precipitate was formed as a result of the use of the solubilizing agent, and the solubilizing agent did not contribute to the prevention of precipitation, and the liquid composition prepared by the method of the present invention was precipitated for more than 60 days in each set of experiments (except for 57 days when polysorbate 80 was added as in example 6), and it was seen that the liquid composition of the present invention was able to significantly increase the solubility of poorly soluble substances, effectively prevent precipitation, and was significantly superior to comparative example 1.
Test example 2 stability test
The lamivudine solutions in the liquid pharmaceutical compositions prepared according to example 10 and comparative example 1 were stable at +5 ℃, +25 ℃ and +40 ℃ for 12 months, respectively. The concentration of lamivudine and its degradation products, compound 1 (structure shown in figure 1) and compound 2 (structure shown in figure 2), was determined by HPLC-UV detection. The results are shown in tables 2 to 5 below, expressed as nominal concentrations of lamivudine (% of the indicated amounts).
TABLE 2
A liquid pharmaceutical composition was prepared according to example 10.
Figure BDA0002921834910000091
TABLE 3
A liquid pharmaceutical composition was prepared according to example 10.
Figure BDA0002921834910000092
TABLE 4
A liquid pharmaceutical composition was prepared according to example 10.
Figure BDA0002921834910000093
TABLE 5
A liquid pharmaceutical composition was prepared according to comparative example 1.
Figure BDA0002921834910000101
TABLE 6
A liquid pharmaceutical composition was prepared according to comparative example 1.
Figure BDA0002921834910000102
TABLE 7
A liquid pharmaceutical composition was prepared according to comparative example 1.
Figure BDA0002921834910000103
The results show that the formulations according to the invention (tables 2 to 4) are more stable than the comparative solutions (tables 5 to 7) under all storage conditions. In the control solution, lamivudine was largely degraded to the primary degradation product compound 1 and partially further degraded to the secondary degradation product compound 2. It is therefore not possible to obtain a mass balance between lamivudine and degradation products for the reference solution.
Test example 3 pharmacokinetics
1. Reagent
Lamivudine reference, available from the university of Sichuan, Wash institute of pharmacy, national institute of medicine, chemistry, lot number 20190102; liquid pharmaceutical compositions prepared in examples 1 to 10 and comparative example 1; manufactured by Heputin Kurarian Schk pharmaceutical Co., Ltd, under the batch number of 05070020, the specification of 240 mL/bottle.
2. Material
The healthy rats (provided by the animal center of basic medical college of Sichuan university) were 18, weighed 170-.
3. Animal test model and selection of administration mode
An ideal animal model would be a pharmacokinetic study after gastric gavage in rats. The experiment adopts rat intragastric administration, aims to investigate the blood parameters of the drug in the rat body, and further studies whether the metabolic processes of the liquid composition and the Heptadine oral solution in the rat body have significant difference. The test adopts the mode of intragastric administration. Generally, the intragastric administration volume of the rat is about 2mL, and according to the literature report and the pre-test result, better detection sensitivity and analysis result can be obtained when the administration amount is about 1500mL/kg (the effective dose is 13.5 mg/kg). In this calculation, about 300mL (effective dose: 2.7mg) was administered to a rat of about 200 g.
4. Test method
The rats are adaptively fed for 4 days before the test, and drinking water is not forbidden in the whole process; weighing the body weight, calculating by 36mL/kg, respectively taking blood from the wound surface of the self-broken tail after 30min, 45min, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h after the intragastric administration, and taking plasma after the blood sample is anticoagulated by heparin sodium. Storing in a refrigerator at-24 deg.C.
5. Measurement of blood concentration
Plasma sample determination the collected plasma samples are taken, liquid chromatography detection is carried out on the collected plasma samples and a reference substance lamivudine solution (100 mug/mL), the absorption peak position of lamivudine is judged, the content of lamivudine in the plasma samples is obtained according to the comparison of the absorption peak area and the reference substance, the data of the blood concentration of lamivudine in three groups of rats over time are respectively shown in table 8, and the mean value drug-time curve is respectively shown in fig. 3.
TABLE 8
Figure BDA0002921834910000111
From the mean blood concentration-time curve (fig. 3), it can be seen that the peak time of lamivudine after gavage administration of the liquid composition of example 10 was about 45min, a higher blood concentration was achieved at about 30min, and lamivudine in plasma was almost completely eliminated after 10 hours, and thus it can be seen that the liquid composition prepared in example 10 of the present invention was rapidly absorbed and the peak time was short after gavage administration. Is obviously superior to the common Heptadine oral liquid and the proportion 1.
Using N, N-dialkyl imidazole as cation and BF4-The ionic liquid which is anion has incomparable advantages of other ionic liquids, such as stability to air and water, wider liquid temperature range, low coordination capacity and the like, the medicinal active component-ionic liquid is formed by pairing medicament ions and counter-charged counter ions, compared with the traditional solid-state form medicament, the ionic liquid has certain advantages in the aspects of solubility, bioavailability, permeability and the like, and after the medicament is converted from a solid crystal form to a room-temperature ionic liquid form, the medicament polymorphic form can be eliminated, and the stability and the bioavailability of the medicament are improved, and the ionic liquid concretely comprises the following components in percentage by weight: 1. increasing the solubility of the pharmaceutically active ingredient; 2. solving the problem of polymorphism of the medicinal active ingredients; 3. improving the biomembrane passing ability of the medicinal active ingredients; 4. is applied to multi-component compound preparations. In the invention, N-dialkyl imidazole is used asCationic, with BF4-The ionic liquid which is anion is applied to the preparation of the liquid composition of the active drug lamivudine which is insoluble in water, the ionic liquid perfectly solves the problem of poor solubility of the lamivudine solvent by better two-phase solubility, the bioavailability is further improved, and the exertion of the drug effect is accelerated.
Compared with the prior art, because the solubility of the lamivudine is poor, the ionic liquid is adopted to dissolve the lamivudine, the solubility of the medicinal active ingredient is increased, and the biomembrane passing property of the medicinal active ingredient is improved, so that the bioavailability of the lamivudine is improved, and the drug effect is accelerated;
according to the invention, the selection of the spray pump and the dosing pump: the dosage forms for nasal administration include nasal drops, aerosols, sprays, gels, microspheres, microparticles and nanoparticles, liposomes and emulsions. According to the convenience of clinical medication, the feasibility of industrial production and the comprehensive analysis of the characteristics of the preparation formulation, the spray and the nasal drops are preferred in the invention. Preferred compositions of the invention have good drug absorption characteristics.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (10)

1. A liquid pharmaceutical formulation of lamivudine, which is characterized by consisting of the following components:
an effective amount of micronized lamivudine or a pharmaceutically acceptable salt thereof;
an ionic liquid;
an absorption enhancer;
water;
and optionally the following ingredients: acid-base regulator, osmotic pressure regulator, thickener and antiseptic;
the ionic liquid is an alkyl imidazole ionic liquid and has a structure shown in a formula I:
Figure FDA0002921834900000011
wherein R is1，R2H, C1-C5 alkyl.
2. A liquid pharmaceutical formulation of lamivudine as claimed in claim 1, wherein the absorption enhancer is selected from one or more of methyl- β -cyclodextrin, dimethyl- β -cyclodextrin, hydroxypropyl- β -cyclodextrin, sulfomethyl ether- β -cyclodextrin, maltosyl- β -cyclodextrin, and lauryl nitrogen.
3. A liquid pharmaceutical formulation of lamivudine as claimed in claim 1, wherein the lamivudine or the pharmaceutically acceptable salt thereof comprises a salt of lamivudine with an organic acid or an inorganic acid.
4. A liquid pharmaceutical formulation of lamivudine as claimed in claim 3, wherein the lamivudine or the pharmaceutically acceptable salt thereof comprises a salt of lamivudine with citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid or nitric acid.
5. A liquid pharmaceutical formulation of lamivudine as claimed in claim 1, wherein the pH modifier is selected from one or more of citric acid, lactic acid, malic acid, fumaric acid, tartaric acid, succinic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, sodium hydroxide and potassium hydroxide; the preservative is selected from one or more of methyl paraben, ethyl paraben, propyl paraben, butyl paraben, sodium benzoate, benzyl alcohol and chlorobutanol; the osmotic pressure regulator is selected from one or more of sodium chloride, glucose, boric acid and borax; the thickening agent is one or a mixture of more of carbomer, cross-linked sodium polyacrylate, poloxamer, polyvinyl alcohol, sodium alginate, glycerol and propylene glycol.
6. A liquid pharmaceutical formulation of lamivudine according to claim 1, wherein the liquid pharmaceutical composition comprises 0.1 to 20 wt% of lamivudine or a pharmaceutically acceptable salt thereof.
7. A liquid pharmaceutical formulation of lamivudine as claimed in claim 1, wherein one dose of the pharmaceutical liquid composition is in the range of 1ml to 10 ml.
8. A liquid pharmaceutical formulation of lamivudine according to claim 1, having the following formulation:
formula 1: 300mg of micronized lamivudine, 0.5g of lactic acid, 0.5g of laurocapram, 1.0g of sodium alginate, 0.1g of ethylparaben, 5g of glucose, 7g of ionic liquid and 100g of water; the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the ionic liquid, adding lactic acid, glucose, laurocapram, sodium alginate and ethylparaben into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain a liquid composition; or the like, or, alternatively,
and (2) formula: 500mg of micronized lamivudine, 2.5g of maltosyl-beta-cyclodextrin, 0.1g of methyl paraben, 2g of glycerol, 1.2g of malic acid, 0.9g of sodium chloride, 10g of ionic liquid and 100g of water; the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the ionic liquid, adding malic acid, sodium chloride, maltosyl-beta-cyclodextrin, glycerol and methyl paraben into a proper amount of distilled water, stirring uniformly and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain a liquid composition; or the like, or, alternatively,
and (3) formula: 900mg of micronized lamivudine, 2.5g of maltosyl-beta-cyclodextrin, 0.1g of sodium benzoate, 2g of carbomer, 1.9g of fumaric acid, 0.1g of sodium hydroxide, 0.9g of sodium chloride, 10g of ionic liquid and 100g of water; the preparation method of the composition of the formula comprises the following steps: dissolving the micronized lamivudine in the amount into ionic liquid, adding fumaric acid, sodium hydroxide, sodium chloride, dimethyl-beta-cyclodextrin, carbomer and sodium benzoate into a proper amount of distilled water, fully stirring and completely dissolving, mixing the ionic liquid and the solution, and finally adding distilled water to 100ml to obtain a liquid composition, thus obtaining the liquid composition.
9. A liquid pharmaceutical formulation of lamivudine as claimed in claim 1, in the form of a nasal administration.
10. A liquid pharmaceutical formulation of lamivudine as claimed in claim 9, which is a nasal spray or nasal drops.
CN202110120405.9A 2021-01-28 2021-01-28 Liquid pharmaceutical formulation of lamivudine Withdrawn CN112891307A (en)

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