CN109419772B - Method and pharmaceutical composition for treating mental disorders by nasal administration - Google Patents
Method and pharmaceutical composition for treating mental disorders by nasal administration Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
Abstract
The present invention relates to a method and a pharmaceutical composition for treating mental disorders by nasal administration. In particular, the present invention relates to a pharmaceutical composition in liquid form comprising: antipsychotic drugs, organic acids, amino acids, ethanol, optional bacteriostatic agents, water and the like. The invention also relates to processes for the preparation of said pharmaceutical compositions and to their use in the preparation of antipsychotic agents, for example in the form of formulations for nasal administration; further, the psychosis is schizophrenia. The method and the pharmaceutical composition for treating mental diseases through nasal administration of the invention can enable the medicine to be absorbed more quickly and have excellent bioavailability.
Description
Technical Field
The invention belongs to the technical field of medicines, in particular to the technical field of preparations for treating mental diseases by nasal administration. In particular to a method for treating mental diseases by nasal administration, and also relates to a pharmaceutical composition for treating mental diseases by nasal administration.
Background
Among the diseases related to the central nervous system, psychiatric diseases are a clinically important group of diseases, and thus a number of antipsychotic drugs have been developed clinically. Antipsychotic (Qiangning drug) has obvious effect on controlling the symptoms of severe psychosis, and is suitable for treating schizophrenia and organic psychosis with mania-depression.
Risperidone (Risperidone) is a new generation of atypical antipsychotic, and has obvious curative effects on positive and negative symptoms of schizophrenia. Risperidone is a potent D2 antagonist for the treatment of acute and chronic schizophrenia as well as other significant positive symptoms (e.g., hallucinations, delusions, thought disorder, enemies, suspicions) and significant negative symptoms (e.g., unresponsiveness, apathy and social apathy, whisper) of various psychotic states. Risperidone is useful for the treatment of manic episodes of bipolar affective disorders manifested by mood elevation, exaggeration or irritability, overestimation, decreased sleep requirements, increased speech rate, thoughtful libido, distraction, or low judgment (including disorganized or overactive behavior). The chemical name of risperidone is 3- [2- [4- (6-fluoro-1, 2-benzisoxazol-3-yl) -1-piperidinyl ] ethyl ] -6,7,8, 9-tetrahydro-2-methyl-4H-pyrido [1,2- α ] pyrimidin-4-one, the molecular formula is C23H27FN4O2, the molecular weight is 410.49, and the chemical structural formula is as follows:
risperidone is white powder or crystalline powder, and has the advantages of small dosage, definite curative effect and small side effect of extrapyramidal system, so that risperidone is widely used in clinic as a first-line medicament for treating schizophrenia. At present, risperidone is marketed into dosage forms such as oral tablets, oral solutions, orally disintegrating tablets, capsules and the like.
Olanzapine (Olanzapine) is an atypical anti-schizophrenia drug primarily used for the treatment of schizophrenia and other psychoses with severe positive symptoms (e.g., delusions, hallucinations, thought disorders, hostility and suspicion) and also with partial efficacy in the acute phase and maintenance of negative symptoms (e.g., apathy, affective and social withdrawal, poverty). Olanzapine also relieves secondary affective symptoms common to schizophrenia and related diseases. Continuous treatment is required to achieve the initial therapeutic effect. Olanzapine was developed on the basis of the previous generation therapeutic clozapine and was marketed in 1996 under approval by the federal Food and Drug Administration (FDA).
Olanzapine is a yellow crystalline powder with the molecular formula of C17H20N4S, molecular weight of 312.43, chemical name: 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b ] [1,5] benzodiazepine, olanzapine having the following chemical structure:
aripiprazole (Aripiprazole) is a novel atypical anti-schizophrenia drug, has bidirectional regulation effect on DA-ergic nervous system, and is a stabilizer of DA transmitter. Has high affinity with D2, D3, 5-HT1A and 5-HT2A receptors. The anti-schizophrenia effect is produced by partial agonism of D2 and 5-HT1A receptors and antagonism of 5-HT2A receptors. The peak time of the blood concentration of the product after oral administration is
The half-life period is 48-68 hours. Dehydroaripiprazole is the main active metabolite. Aripiprazole is used to treat various types of schizophrenia. The foreign clinical test shows that the product has obvious curative effect on both positive and negative symptoms of schizophrenia, can also improve accompanying emotional symptoms and reduce the recurrence rate of schizophrenia.
The molecular formula of the aripiprazole is C23H27C12N3O2, the molecular weight is 448.39, and the chemical name is: 7- [4- [4- (2, 3-dichlorophenyl) -1-piperazinyl ] butoxy ] -3, 4-dihydroquinolone. The aripiprazole is white or white-like crystalline powder, and has no odor.
In view of the small dosage of these antipsychotic agents and the expectation of convenient use and rapid onset of action, it is clinically important to prepare them as nasal preparations to carry out and implement nasal administration methods for treating mental disorders. For example, CN104398474A discloses a nasal gel of risperidone and its preparation method, wherein the nasal gel contains risperidone, a matrix material, pharmaceutically acceptable water and other pharmaceutically effective adjuvants, such as osmotic pressure regulator, absorption enhancer, antiseptic, humectant, pH regulator, etc. The nasal gel of risperidone is prepared by dissolving risperidone and other pharmaceutically effective auxiliary materials in water in sequence, adding the risperidone and the other pharmaceutically effective auxiliary materials into blank gel matrix in times, and fully and uniformly grinding. The nasal gel is believed to be simple in preparation process, and has the characteristics of remarkable brain targeting property, quick absorption and effect, high bioavailability, good clinical effect, convenience in use and safety. However, since the above nasal gel is a viscous gel-like substance, the viscosity is extremely high, it cannot be dosed by means of a device such as a metered dose spray pump, it can be manually dosed only by means of smearing, the dose of administration is poorly controlled, which is not desirable for such low-dose, strong-effect antipsychotic drugs. Therefore, it is still highly desirable for those skilled in the art to formulate these drugs so that they can be administered nasally by means of a dosing device, for example, by spraying a prescribed amount of a medicinal liquid intranasally to achieve dosing.
Disclosure of Invention
It is an object of the present invention to provide a method for achieving a quantitative administration of an antipsychotic agent by nasal administration by means of a dosing device, for example by spraying a prescribed amount of a liquid medicine into the nose. The method uses a liquid medicine in a form that can be sprayed via a dosing device such as a spray pump, and the liquid medicine after spraying can become viscous rapidly and is not easy to run off, thereby avoiding loss of medicine. The present invention has been accomplished by providing such a specially formulated medical solution.
To this end, a first aspect of the invention provides a pharmaceutical composition in liquid form comprising per 100 ml: 0.05-2.5 g of antipsychotic drug, 0.2-2 g of chitose, 1-5 g of sodium glycerophosphate, 0.5-1.5 g of organic acid, 0.2-1 g of amino acid, 2-5 ml of ethanol, 0-0.5 g of optional bacteriostatic agent and water in balance.
The pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the antipsychotic agent is selected from the group consisting of: risperidone, olanzapine, aripiprazole.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the organic acid is citric acid and/or tartaric acid.
The pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the amino acid is selected from glycine, serine, lysine, or glutamic acid.
The pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the bacteriostatic agent is selected from the group consisting of: chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methylparaben, ethylparaben, propylparaben, butylparaben, and combinations thereof.
The pharmaceutical composition according to any embodiment of the first aspect of the invention, comprising per 100 ml: 0.05-2 g of antipsychotic drug, 0.2-1 g of chitose, 1-2.5 g of sodium glycerophosphate, 0.5-1 g of organic acid, 0.2-1 g of amino acid, 2-4 ml of ethanol, 0.005-0.5 g of bacteriostatic agent and water in balance.
In describing the amount of water in the pharmaceutical composition of the present invention, it is expressed in the form of "adding water to balance", that is, if 100ml of the pharmaceutical composition is prepared, after weighing or measuring other materials and preparing a liquid medicine with an appropriate amount of water, adding water until the total volume of the pharmaceutical composition reaches 100 ml. This expression and the manner of its operation are well known to those skilled in the art of pharmaceutical formulation.
The pharmaceutical composition according to any one of the embodiments of the first aspect of the present invention is a flowable liquid after being left at a temperature of less than or equal to 32 ℃ for 1 hour. The pharmaceutical composition according to the first aspect of the present invention is a flowable liquid after being left at a temperature of 5 to 32 ℃ for 1 hour. The term "flowable liquid" refers to a liquid that is determined and judged to be flowable according to the fluidity test method of the present invention.
The pharmaceutical composition according to any one of the embodiments of the first aspect of the present invention is a semi-solid, non-flowable hydrogel after being placed at a temperature higher than or equal to 34 ℃ for 30 min. The pharmaceutical composition according to any one of the embodiments of the first aspect of the present invention is a non-flowable semi-solid hydrogel after being placed at a temperature of 34-42 ℃ for 30 min. The term "non-flowable semi-solid hydrogel" refers to a semi-solid hydrogel that is determined and judged to be non-flowable according to the flowability assay of the present invention.
In general, the various compositions of the present invention may change to flowable liquids when left at room temperature, e.g. at a temperature of 25 ± 5 ℃, for a sufficiently long period of time, e.g. above 2 hours or, e.g. above 5 hours or, e.g. above 10 hours or longer, e.g. above 24 hours. Thus, in the present invention, the fluidity measurement method is measured by:
(a) taking an appropriate amount of a test substance (e.g., a pharmaceutical composition of the present invention, which may be in the form of a flowable liquid or a non-flowable semi-solid hydrogel), and allowing it to liquefy to a flowable liquid at a temperature of 25 ± 5 ℃ for a suitable period of time (e.g., more than 2 hours or, e.g., more than 5 hours or, e.g., more than 10 hours or longer, e.g., more than 24 hours);
(b) taking 1g of the test object which is flowable liquid, placing the test object at the bottom of a 10ml test tube with a plug scale (about occupying 1ml of volume), and marking the test tube scale from the bottom of the test tube to the opening direction;
(c) sealing the test tube, and standing at a specified temperature for a proper time to make the test object show a stable physical state at the temperature;
(d) the tube is then inverted and left to stand for a suitable period of time, and the body fraction of the test article (i.e. more than 50% of the test article, as can be readily determined by visual inspection) is visually observed to see if it has flowed down the tube wall to determine if it is flowable:
(d1) if the test object body portion has at least flowed down to the 5ml mark, then the test object is considered to be a flowable liquid at said specified temperature of step (c);
(d2) if the body portion of the test article does not flow at least 2ml of the graduation mark, the test article is considered to be a non-flowable semi-solid hydrogel at the prescribed temperature in step (c).
The pharmaceutical composition according to any one of the embodiments of the first aspect of the present invention, which is measured by the flowability assay method of the present invention, in step (c), the sealed test tube is left at a temperature of 32 ℃ or lower for 1 hour, particularly at a temperature of 5 to 32 ℃ for 1 hour, and then the subsequent steps are performed and observed. In general, pharmaceutical compositions having features of the invention, when so tested, demonstrate flowable liquids.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, which is measured by the flowability assay method of the present invention, in step (c), the sealed test tube is left at a temperature higher than or equal to 34 ℃ for 30min, particularly at a temperature of 34 to 42 ℃ for 30min, and then the subsequent steps are performed and observed. In general, pharmaceutical compositions having features of the invention, when so tested, demonstrate a semi-solid hydrogel that is non-flowable.
According to the above-mentioned fluidity test method of the present invention, it is also possible to measure the gel time (which can be recorded as t1 in the present invention) of the process of the pharmaceutical composition of the present invention changing from a flowable liquid to a non-flowable semi-solid hydrogel under the specified temperature conditions, after simple modification, that is: for example, in the determination step (c), the composition is allowed to stand at a defined temperature (T1) (e.g., a temperature greater than or equal to 34 ℃, particularly, e.g., 34 ℃ to 42 ℃) for a certain period of time (T1) until the composition exhibits a non-flowable semi-solid hydrogel in step (d2), and the above-mentioned period of time T1 is recorded as the gel time at the temperature T1.
The pharmaceutical composition according to any one of the embodiments of the first aspect of the present invention has a gel time of 0.5 to 10min, in particular of 0.5 to 2min, at a temperature higher than or equal to 34 ℃ (in particular, for example, at a temperature of 34 to 42 ℃, for example, at a temperature of 36 ℃).
According to the above-mentioned fluidity test method of the present invention, it is also possible to measure the decondensation time (which can be denoted as t2 in the present invention) of the process of the pharmaceutical composition of the present invention changing from a non-flowable semi-solid hydrogel to a flowable liquid under the specified temperature conditions, after simple modification, namely: for example, in the determination step (c), the composition is allowed to stand at a gellable temperature (e.g., a temperature greater than or equal to 34 ℃, particularly, e.g., 34-42 ℃) to fully gel the composition (typically, e.g., sufficient to stand for more than 2 hours), and then the composition is allowed to stand at a prescribed temperature (T2) (typically, less than or equal to 32 ℃, particularly, 5-32 ℃) for a certain period of time (T2) until the composition appears to be a flowable liquid in step (d1), and the above-mentioned period of time T2 is recorded as the time to decondensation at the temperature of T2.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention has a decondensation time of 5 to 30min, in particular of 5 to 15min at a temperature lower than or equal to 32 ℃ (in particular, for example, at a temperature of 5 to 32 ℃, for example, at a temperature of 20 ℃).
It has been unexpectedly found that the medicinal liquid prepared from the medicinal composition of the present invention by combining chitosan, sodium glycerophosphate, organic acid, glycine and ethanol can be used to obtain the composition with the characteristics of the present invention, for example, the composition can be converted into liquid with good fluidity at a faster speed when the composition is gelled at high temperature and then returns to a low temperature, and the problems that the medicinal liquid is difficult to return to the liquid with good fluidity when the composition is gelled at high temperature and the subsequent administration is difficult, such as the blockage of the channel of a spray pump during the spray administration, so that the medicinal liquid cannot be dosed are avoided.
The pharmaceutical composition according to any one of the embodiments of the first aspect of the present invention, which is filled in a vial equipped with a spray pump. Thereby facilitating the administration through nasal spray.
A pharmaceutical composition according to any one of the embodiments of the first aspect of the invention, which is prepared by a process comprising the steps of:
a) dissolving chitose, organic acid and glycine with sufficient water to obtain solution;
b) suspending the antipsychotic drug in ethanol, slowly adding into the solution obtained in the previous step, stirring for dissolving, sterilizing under hot pressure, and cooling in ice water bath for at least 30 min;
c) dissolving sodium glycerophosphate and an optional bacteriostatic agent in a proper amount of water for injection to prepare a solution containing 30-40% of sodium glycerophosphate, filtering the solution through a 0.22 mu m filter membrane for sterilization, and cooling the solution in an ice-water bath for at least 30min for later use;
d) slowly adding the solution obtained in the step c) into the solution obtained in the step b) in an ice bath under stirring, adding water to full amount, and fully stirring and mixing to obtain the pharmaceutical composition in a liquid form, wherein the pharmaceutical composition is optionally further filled into a medicine bottle provided with a spray pump.
The pharmaceutical composition according to any embodiment of the first aspect of the invention, when manufactured, wherein the steps are performed under sterile conditions. In particular, wherein step d) is carried out under sterile conditions. In one embodiment, after adding all the materials at the end of step d) and stirring them uniformly, the resulting liquid medicine is sterilized with a 0.22 μm filter.
A pharmaceutical composition according to any embodiment of the first aspect of the invention having a formulation as described in any example in the detailed description section below.
A pharmaceutical composition according to any embodiment of the first aspect of the invention having a formulation and a process as described in any example in the detailed description section below.
Further, the present invention provides in a second aspect a process for the preparation of a pharmaceutical composition, for example according to any of the embodiments of the first aspect of the present invention, comprising per 100 ml: 0.05-2.5 g of antipsychotic drugs, 0.2-2 g of chitose, 1-5 g of sodium glycerophosphate, 0.5-1.5 g of organic acid, 0.2-1 g of amino acid, 2-5 ml of ethanol, 0-0.5 g of optional bacteriostatic agent and water in balance; the method comprises the following steps:
a) dissolving chitose, organic acid and glycine with sufficient water to obtain solution;
b) suspending the antipsychotic drug in ethanol, slowly adding into the solution obtained in the previous step, stirring for dissolving, sterilizing under hot pressure, and cooling in ice water bath for at least 30 min;
c) dissolving sodium glycerophosphate and an optional bacteriostatic agent in a proper amount of water for injection to prepare a solution containing 30-40% of sodium glycerophosphate, filtering the solution through a 0.22 mu m filter membrane for sterilization, and cooling the solution in an ice-water bath for at least 30min for later use;
d) slowly adding the solution obtained in the step c) into the solution obtained in the step b) in an ice bath under stirring, adding water to full amount, and fully stirring and mixing to obtain the pharmaceutical composition in a liquid form, wherein the pharmaceutical composition is optionally further filled into a medicine bottle provided with a spray pump.
The method according to any embodiment of the second aspect of the invention, wherein the antipsychotic agent is selected from: risperidone, olanzapine, aripiprazole.
The method according to any embodiment of the second aspect of the present invention, wherein the organic acid is citric acid and/or tartaric acid.
The pharmaceutical composition according to any embodiment of the first aspect of the invention, wherein the amino acid is selected from glycine, serine, lysine, or glutamic acid.
A method according to any embodiment of the second aspect of the invention, wherein the bacteriostatic agent is selected from: chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methylparaben, ethylparaben, propylparaben, butylparaben, and combinations thereof.
The method according to any embodiment of the second aspect of the invention, said pharmaceutical composition comprises per 100 ml: 0.05-2 g of antipsychotic drug, 0.2-1 g of chitose, 1-2.5 g of sodium glycerophosphate, 0.5-1 g of organic acid, 0.2-1 g of amino acid, 2-4 ml of ethanol, 0.005-0.5 g of bacteriostatic agent and water in balance.
According to the method of any embodiment of the second aspect of the present invention, the pharmaceutical composition is a flowable liquid after being placed at a temperature of less than or equal to 32 ℃ for 1 hour. According to the method of any embodiment of the second aspect of the present invention, the pharmaceutical composition is a flowable liquid after being left at a temperature of 5 to 32 ℃ for 1 hour.
According to the method of any embodiment of the second aspect of the present invention, the pharmaceutical composition is a non-flowable semi-solid hydrogel after being placed at a temperature higher than or equal to 34 ℃ for 30 min. According to the method of any embodiment of the second aspect of the present invention, the pharmaceutical composition is a non-flowable semi-solid hydrogel after being placed at a temperature of 34 to 42 ℃ for 30 min.
According to the method of any of the embodiments of the second aspect of the present invention, the pharmaceutical composition is allowed to stand at a temperature of 32 ℃ or lower, particularly at a temperature of 5 to 32 ℃ for 1 hour in step (c) when measured by the flowability assay method of the present invention, and then the subsequent steps are performed and observed. In general, pharmaceutical compositions having features of the invention, when so tested, demonstrate flowable liquids.
According to the method of any of the embodiments of the second aspect of the present invention, the pharmaceutical composition is allowed to stand at a temperature higher than or equal to 34 ℃ for 30min, particularly at a temperature of 34 to 42 ℃ for 30min in step (c) when measured by the flowability assay of the present invention, and then the subsequent steps are performed and observed. In general, pharmaceutical compositions having features of the invention, when so tested, demonstrate a semi-solid hydrogel that is non-flowable.
According to the method of any embodiment of the second aspect of the present invention, the pharmaceutical composition has a gel time of 0.5 to 10min, in particular 0.5 to 2min, at a temperature higher than or equal to 34 ℃ (in particular, for example, at a temperature of 34 to 42 ℃, for example, at a temperature of 36 ℃).
According to the method of any embodiment of the second aspect of the invention, the pharmaceutical composition has a decondensation time of 5-30 min, in particular of 5-15 min, at a temperature lower than or equal to 32 ℃ (in particular, for example, at a temperature of 5-32 ℃, for example at a temperature of 20 ℃).
According to the method of any embodiment of the second aspect of the invention, the pharmaceutical composition is filled in a vial equipped with a spray pump. Thereby facilitating the administration through nasal spray.
The method according to any embodiment of the second aspect of the invention, wherein each step is performed under sterile conditions. In particular, wherein step d) is carried out under sterile conditions. In one embodiment, after adding all the materials at the end of step d) and stirring them uniformly, the resulting liquid medicine is sterilized with a 0.22 μm filter.
According to a method of any embodiment of the second aspect of the invention, the pharmaceutical composition has a formulation as described in any of the examples in the detailed description section below.
The pharmaceutical composition according to the method according to any embodiment of the second aspect of the invention has the formulation and the preparation as described in any of the examples in the detailed description section below.
Still further, a third aspect of the present invention provides the use of a pharmaceutical composition according to any of the embodiments of the first aspect of the present invention or a pharmaceutical composition prepared by a process according to any of the second aspects of the present invention for the manufacture of an antipsychotic agent (e.g. in the form of a formulation for nasal administration).
The use according to the third aspect of the invention, wherein the psychosis is schizophrenia.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
In the present invention, when ethanol is mentioned, it means ethanol that meets the pharmaceutical standards, for example, ethanol recorded in the second division of "chinese pharmacopoeia" 2015 edition, unless otherwise specified.
In general, the present invention relates to the design and manufacture of a pharmaceutical composition containing an antipsychotic agent that can be administered nasally by nebulization, and its use. Particularly, the preparation in a liquid form is flowable liquid at room temperature and can be converted into a semisolid gel form at or close to physiological temperature by taking common anti-schizophrenia medicines such as risperidone, olanzapine, aripiprazole and the like as main medicines and adjusting the types and the dosage of auxiliary materials such as chitose, sodium glycerophosphate and the like, so that the loss of the medicines in nasal cavities is avoided, and the preparation has remarkable advantages in the treatment of diseases.
In addition, clinical applicability of the pharmaceutical formulation is of particular concern because of the high temperatures to which the pharmaceutical formulation may be exposed occasionally during storage and transportation after manufacture, for example, up to 35 ℃, and the short exposure to high temperatures causes the pharmaceutical formulation, which is originally in a liquid state, to gel into a non-flowable semi-solid. The present inventors have surprisingly found that the addition of specific organic acids and glycine to the present composition in appropriate amounts allows for a composition which gels and appears non-flowable on exposure to high temperatures, and which when disposed of again at lower temperatures, can re-form a free-flowing liquid in a shorter time, which is of great value for the present composition requiring metered nasal administration via a spray pump.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible.
In the specific examples of the compositions prepared below, the total amount of the preparation per preparation was 2000ml or more, although in the case of the formulations, it is convenient to list the amount of the preparation per 100 ml. In the present invention, the spray pumps used are of the same specification/manufacturer, as not otherwise specified.
A. Test methods examples section
Test method example 1: fluidity test method of the pharmaceutical composition of the present invention
Generally, the pharmaceutical compositions of the present invention are flowable liquids after 1 hour at a temperature of less than or equal to 32 ℃ (e.g., 5-32 ℃) and non-flowable semi-solid hydrogels after 30 minutes at a temperature of greater than or equal to 34 ℃ (e.g., 34-42 ℃).
The above-mentioned "flowable liquid" and "non-flowable semi-solid hydrogel" can be measured and judged according to the fluidity test method of the present invention.
In the present invention, the fluidity measurement method is determined by:
(a) taking an appropriate amount of a test substance (e.g., a pharmaceutical composition of the present invention, which may be in the form of a flowable liquid or a non-flowable semi-solid hydrogel), and allowing it to liquefy to a flowable liquid at a temperature of 25 ± 5 ℃ for a suitable period of time (e.g., more than 2 hours or, e.g., more than 5 hours or, e.g., more than 10 hours or longer, e.g., more than 24 hours);
(b) taking 1g of the test object which is flowable liquid, placing the test object at the bottom of a 10ml test tube with a plug scale (about occupying 1ml of volume), and marking the test tube scale from the bottom of the test tube to the opening direction;
(c) sealing the test tube, and standing at a specified temperature for a proper time to make the test object show a stable physical state at the temperature;
(d) the tube is then inverted and left to stand for a suitable period of time, and the body fraction of the test article (i.e. more than 50% of the test article, as can be readily determined by visual inspection) is visually observed to see if it has flowed down the tube wall to determine if it is flowable:
(d1) if the test object body portion has at least flowed down to the 5ml mark, then the test object is considered to be a flowable liquid at said specified temperature of step (c);
(d2) if the body portion of the test article does not flow at least 2ml of the graduation mark, the test article is considered to be a non-flowable semi-solid hydrogel at the prescribed temperature in step (c).
The pharmaceutical composition of the present invention is, when measured by the flowability measuring method of the present invention, allowed to stand at a temperature of 32 ℃ or lower for 1 hour, particularly 5 to 32 ℃ for 1 hour in the step (c), and then subjected to the subsequent steps and observed. In general, pharmaceutical compositions having features of the invention, when so tested, demonstrate flowable liquids.
The pharmaceutical composition of the present invention is subjected to a step (c) of leaving the sealed test tube at a temperature of 34 ℃ or higher for 30 minutes, particularly at a temperature of 34 to 42 ℃ for 30 minutes, and then to the subsequent steps and observation, when measured by the fluidity measuring method of the present invention. In general, pharmaceutical compositions having features of the invention, when so tested, demonstrate a semi-solid hydrogel that is non-flowable.
The above-mentioned fluidity test method of the present invention, which is simply modified, can also measure the gel time (which can be recorded as t1 in the present invention) of the process of the pharmaceutical composition of the present invention changing from a flowable liquid to a non-flowable semi-solid hydrogel under the specified temperature conditions, namely: for example, in the determination step (c), the composition is allowed to stand at a defined temperature (T1) (e.g., a temperature greater than or equal to 34 ℃, particularly, e.g., 34 ℃ to 42 ℃) for a certain period of time (T1) until the composition exhibits a non-flowable semi-solid hydrogel in step (d2), and the above-mentioned period of time T1 is recorded as the gel time at the temperature T1. Generally, the pharmaceutical composition has a gel time of 0.5-2 min at a temperature of 36 ℃.
The above-mentioned fluidity test method of the present invention, which is simply modified, can also measure the decondensation time (which can be recorded as t2 in the present invention) of the process of the pharmaceutical composition of the present invention changing from a non-flowable semi-solid hydrogel to a flowable liquid under the specified temperature conditions, namely: for example, in the determination step (c), the composition is allowed to stand at a gellable temperature (e.g., a temperature greater than or equal to 34 ℃, particularly, e.g., 34-42 ℃) to fully gel the composition (typically, e.g., sufficient to stand for more than 2 hours), and then the composition is allowed to stand at a prescribed temperature (T2) (typically, less than or equal to 32 ℃, particularly, 5-32 ℃) for a certain period of time (T2) until the composition appears to be a flowable liquid in step (d1), and the above-mentioned period of time T2 is recorded as the time to decondensation at the temperature of T2. Generally, the pharmaceutical composition according to the present invention has a decondensation time of 5-15 min at a temperature of 20 ℃.
Test method example 2: spray uniformity in relation to dose administered
Due to different densities of liquid medicines in different formulas, although the spraying volume of each pump of the spray pump is marked as 0.1ml, the difficulty in the spraying uniformity test can be well solved when the weight of each spray is used for representing if the liquid spraying amount is determined according to the volume, which is not only troublesome but also not intuitive. The method of this test example is specifically as follows.
For each drug solution, it was filled into a vial equipped with a spray pump (spray pump sprays 0.1ml per pump).
Before the test, the medicine is left to stand at 23-26 ℃ for at least 1 hour, then the medicine is sprayed for 3 times in a standard spraying mode specified by a spraying pump, the spraying medicine bottle containing the medicine liquid is precisely weighed and recorded as initial weight W0, then after the medicine is continuously sprayed for 5 times, the spraying medicine bottle containing the medicine liquid is precisely weighed and recorded as post-spraying weight W1, and the quotient obtained by dividing the difference value of the two weights of W0 and W1 by 5 is used as the weight of the medicine liquid sprayed each time, namely the weight of the medicine liquid sprayed each time. The weight of each spray solution for one test can be obtained according to the method.
Because each bottle of liquid medicine needs to be used for a plurality of times, including being used for a plurality of times, such as 2-3 times, in the same day, one bottle of medicine needs to be used for more than 5 days continuously when being used every day until the liquid medicine in the medicine bottle is exhausted. Therefore, in the above-described manner, the weight of each spray for each test obtained in 6 tests in one day was measured, and the average value and the standard deviation of the weights of the 6 sprays were calculated, from which the RSD was calculated as the intra-day RSD.
In addition, the sample is placed at 36-38 ℃ for 3 hours (gelation occurs) and then placed at 5-8 ℃ for 3 hours (de-coagulation occurs) for the next day of measurement before the measurement, and after the next day of measurement, the sample is subjected to high-low temperature cyclic treatment at 36-38 ℃ and 5-8 ℃ for the next day of measurement; the weight of each spray solution in each test day obtained in 6 days of the test day was continuously measured once a day by the above-mentioned method, and the average value and standard deviation of the weight of each spray solution in 6 days were calculated, from which RSD was calculated as the daytime RSD. Generally, less than 2% and especially less than 1% of the RSD, whether it be daily RSD or daytime RSD, is preferred, such RSD indicating excellent uniformity of administration of the drug.
Test method example 3: biological benefitDegree of use test
Four reagents: the spray obtained in the example 1 of the invention and the commercially available risperidone oral solution are directly orally taken by a spray prepared by filling a spray pump/bottle, a gel composition obtained in the example 1 of CN104398474A and the commercially available risperidone oral solution. The dose is 5 mg/kg.
The test method comprises the following steps: 60 SD male rats with the body weight ranging from 250 g to 300g are selected, fasted for 12h before the test, allowed to drink water freely and randomly divided into 4 groups of 8 rats. Wherein one group of animals is administered risperidone oral liquid by intragastric administration; another group applied gel CN104398474A to rat nose, and allowed the animal to move freely after the nose was kept up for 30 seconds; two other groups of animals were sprayed with two sprays into the nose of the animals, and the animals were allowed to move freely after the animals were sprayed for 30 seconds with the nose facing up.
The above animals were collected via the orbit at the pre-designed blood collection intervals, i.e., 0 (pre-administration), 0.25 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 7.5 hours, 10 hours, 15 hours, and 24 hours, each 0.5mL of blood was placed in a heparinized polyethylene tube, immediately centrifuged, and plasma was isolated. And finally, measuring the blood concentration of risperidone by using a high performance liquid chromatography, drawing a blood concentration-time curve, and calculating main pharmacokinetic parameters by using a non-atrioventricular model method, wherein the main pharmacokinetic parameters comprise an area AUC (acquired blood concentration-time) value under the blood concentration-time curve within 0-24 hours.
The results show that: the peak reaching time of the blood concentration of each animal in the oral risperidone liquid group for intragastric administration is 27-41 min, the peak reaching time of the blood concentration of each animal in the two nasal spray administration groups is 4-7 min, and the peak reaching time of the blood concentration of each animal in the nasal gel composition group is 6-9 min, which shows that the nasal administration is obviously faster than the oral administration absorption; in addition, as a result of dividing the AUC values of the other administration forms/agents by the AUC values of the oral gavage group and multiplying the result by 100% based on the AUC values of the oral gavage group, the relative bioavailability of each combination with respect to the oral group was 173% in the spray group obtained in example 1 of the present invention, 91% in the commercially available risperidone oral solution spray administration group, and 131% in the nasal group of the gel composition. The significantly higher bioavailability of the group of example 1 of the present invention relative to the orally administered group may be due to two reasons, one being that oral absorption is not good and nasal absorption is complete, the other being a formulation factor, and apart from the first possible reason, the spray administration of a commercial oral solution of risperidone may be due to drug loss and exhibit very low bioavailability, while nasal administration of a gel composition may be due to a formulation factor that is lower than that of the present invention. The in vivo research results show that the medicine composition of the invention has the advantages of rapid medicine absorption, obviously improved bioavailability, prolonged action time of the medicine and greatly improved expected clinical curative effect of the medicine.
B. Examples section
Example 1: preparation of the pharmaceutical composition of the invention
The formula is as follows:
| risperidone | 0.5g， |
| Chitosan | 0.5g， |
| Glycerol sodium phosphate | 2g， |
| Citric acid | 0.75g， |
| Glycine | 0.5g， |
| Ethanol | 3ml， |
| Water (W) | Adding proper amount of the mixture to 100 ml; |
preparation (carried out under conditions for the preparation of sterile preparations):
a) dissolving chitose, organic acid and glycine with sufficient water to obtain solution;
b) suspending the antipsychotic drug in ethanol, slowly adding into the solution obtained in the previous step, stirring for dissolving, sterilizing under hot pressure, and cooling in ice water bath for at least 30 min;
c) dissolving sodium glycerophosphate and an optional bacteriostatic agent (when the bacteriostatic agent is added) into a proper amount of water for injection to prepare a solution containing 30-40% of sodium glycerophosphate, filtering the solution through a 0.22 mu m filter membrane for sterilization, and cooling the solution in an ice-water bath for at least 30min for later use;
d) slowly adding the solution obtained in the step c) into the solution obtained in the step b) in an ice bath under stirring, adding water to full amount, fully stirring and mixing to obtain the pharmaceutical composition in a liquid (clear solution) form at room temperature, reserving and using the pharmaceutical composition for the test, and further filling the other half of the pharmaceutical composition into a medicine bottle provided with a spray pump (the spray volume of the spray pump is 0.1 ml).
Fluidity measurement results: the gel time (t1, 36 ℃) is 1.2min, and the decondensation time (t2, 20 ℃) is 9.7 min.
Example 2: preparation of the pharmaceutical composition of the invention
The formula is as follows:
| risperidone | 0.05g， |
| Chitosan | 0.2g， |
| Glycerol sodium phosphate | 1g， |
| Citric acid | 0.5g， |
| Glycine | 0.2g， |
| Ethanol | 2ml， |
| Water (W) | Adding proper amount of the mixture to 100 ml; |
preparation (carried out under conditions for the preparation of sterile preparations):
a) dissolving chitose, organic acid and glycine with sufficient water to obtain solution;
b) suspending the antipsychotic drug in ethanol, slowly adding into the solution obtained in the previous step, stirring for dissolving, sterilizing under hot pressure, and cooling in ice water bath for at least 30 min;
c) dissolving sodium glycerophosphate and an optional bacteriostatic agent (when the bacteriostatic agent is added) into a proper amount of water for injection to prepare a solution containing 30-40% of sodium glycerophosphate, filtering the solution through a 0.22 mu m filter membrane for sterilization, and cooling the solution in an ice-water bath for at least 30min for later use;
d) slowly adding the solution obtained in the step c) into the solution obtained in the step b) in an ice bath under stirring, adding water to full amount, fully stirring and mixing to obtain the pharmaceutical composition in a liquid (clear solution) form at room temperature, reserving and using the pharmaceutical composition for the test, and further filling the other half of the pharmaceutical composition into a medicine bottle provided with a spray pump (the spray volume of the spray pump is 0.1 ml).
Fluidity measurement results: the gel time (t1, 36 ℃) is 0.7min, and the decondensation time (t2, 20 ℃) is 13.2 min.
Example 3: preparation of the pharmaceutical composition of the invention
The formula is as follows:
preparation (carried out under conditions for the preparation of sterile preparations):
a) dissolving chitose, organic acid and glycine with sufficient water to obtain solution;
b) suspending the antipsychotic drug in ethanol, slowly adding into the solution obtained in the previous step, stirring for dissolving, sterilizing under hot pressure, and cooling in ice water bath for at least 30 min;
c) dissolving sodium glycerophosphate and an optional bacteriostatic agent (when the bacteriostatic agent is added) into a proper amount of water for injection to prepare a solution containing 30-40% of sodium glycerophosphate, filtering the solution through a 0.22 mu m filter membrane for sterilization, and cooling the solution in an ice-water bath for at least 30min for later use;
d) slowly adding the solution obtained in the step c) into the solution obtained in the step b) in an ice bath under stirring, adding water to full amount, fully stirring and mixing to obtain the pharmaceutical composition in a liquid (clear solution) form at room temperature, reserving and using the pharmaceutical composition for the test, and further filling the other half of the pharmaceutical composition into a medicine bottle provided with a spray pump (the spray volume of the spray pump is 0.1 ml).
Fluidity measurement results: the gel time (t1, 36 ℃) is 0.9min, and the decondensation time (t2, 20 ℃) is 14.4 min.
Example 4: preparation of the pharmaceutical composition of the invention
The formula is as follows:
| risperidone | 2.5g， |
| Chitosan | 2g， |
| Glycerol sodium phosphate | 5g， |
| Citric acid | 1g， |
| Glycine | 0.75g， |
| Ethanol | 4ml， |
| Water (W) | Adding proper amount of the mixture to 100 ml; |
preparation (carried out under conditions for the preparation of sterile preparations):
a) dissolving chitose, organic acid and glycine with sufficient water to obtain solution;
b) suspending the antipsychotic drug in ethanol, slowly adding into the solution obtained in the previous step, stirring for dissolving, sterilizing under hot pressure, and cooling in ice water bath for at least 30 min;
c) dissolving sodium glycerophosphate and an optional bacteriostatic agent (when the bacteriostatic agent is added) into a proper amount of water for injection to prepare a solution containing 30-40% of sodium glycerophosphate, filtering the solution through a 0.22 mu m filter membrane for sterilization, and cooling the solution in an ice-water bath for at least 30min for later use;
d) slowly adding the solution obtained in the step c) into the solution obtained in the step b) in an ice bath under stirring, adding water to full amount, fully stirring and mixing to obtain the pharmaceutical composition in a liquid (clear solution) form at room temperature, reserving and using the pharmaceutical composition for the test, and further filling the other half of the pharmaceutical composition into a medicine bottle provided with a spray pump (the spray volume of the spray pump is 0.1 ml).
Fluidity measurement results: the gel time (t1, 36 ℃) is 1.8min, and the decondensation time (t2, 20 ℃) is 5.3 min.
Example 5: preparation of the pharmaceutical composition of the invention
The formula is as follows:
| risperidone | 1g， |
| Chitosan | 1.5g， |
| Glycerol sodium phosphate | 2g， |
| Citric acid | 0.8g， |
| Glycine | 0.5g， |
| Ethanol | 3ml， |
| Water (W) | Adding proper amount of the mixture to 100 ml; |
preparation (carried out under conditions for the preparation of sterile preparations):
a) dissolving chitose, organic acid and glycine with sufficient water to obtain solution;
b) suspending the antipsychotic drug in ethanol, slowly adding into the solution obtained in the previous step, stirring for dissolving, sterilizing under hot pressure, and cooling in ice water bath for at least 30 min;
c) dissolving sodium glycerophosphate and an optional bacteriostatic agent (when the bacteriostatic agent is added) into a proper amount of water for injection to prepare a solution containing 30-40% of sodium glycerophosphate, filtering the solution through a 0.22 mu m filter membrane for sterilization, and cooling the solution in an ice-water bath for at least 30min for later use;
d) slowly adding the solution obtained in the step c) into the solution obtained in the step b) in an ice bath under stirring, adding water to full amount, fully stirring and mixing to obtain the pharmaceutical composition in a liquid (clear solution) form at room temperature, reserving and using the pharmaceutical composition for the test, and further filling the other half of the pharmaceutical composition into a medicine bottle provided with a spray pump (the spray volume of the spray pump is 0.1 ml).
Fluidity measurement results: the gel time (t1, 36 ℃) is 0.5min, and the decondensation time (t2, 20 ℃) is 7.6 min.
Example 6: preparation of the pharmaceutical composition of the invention
Referring to the formulations and methods of examples 1-5, respectively, except that the active ingredient was replaced with an equal amount of olanzapine, five compositions were obtained, whose flowability measurements were: the gel time (t1, 36 ℃) is 0.5-2 min, and the de-gel time (t2, 20 ℃) is 5-15 min.
Example 7: preparation of the pharmaceutical composition of the invention
With reference to the formulations and the preparation processes of examples 1 to 5, respectively, except that the active ingredients therein were replaced with the same amount of aripiprazole to obtain five compositions whose results of the fluidity measurement were: the gel time (t1, 36 ℃) is 0.5-2 min, and the de-gel time (t2, 20 ℃) is 5-15 min.
Example 8: preparation of the pharmaceutical composition of the invention
Five compositions were obtained by reference to the formulations and methods of examples 1 to 5, respectively, except that citric acid was replaced by an equal amount of tartaric acid, and the results of the fluidity test were: the gel time (t1, 36 ℃) is 0.5-2 min, and the de-gel time (t2, 20 ℃) is 5-15 min.
Example 9: preparation of the pharmaceutical composition of the invention
Referring to the formulation and preparation of example 1, except that the following amounts of bacteriostatic agent were also added to each of the five different formulations: 0.005g of chlorobutanol, 0.1g of thimerosal, 0.05g of benzalkonium chloride, 0.05g of benzalkonium bromide, and 0.2g of ethylparaben/0.25 g of propylparaben, to give five compositions whose flowability assay results: the gel time (t1, 36 ℃) is 0.5-2 min, and the de-gel time (t2, 20 ℃) is 5-15 min.
In addition, all the pharmaceutical compositions obtained in the above examples 1 to 9 are flowable liquids after being placed at a temperature of 5 to 32 ℃ for 1 hour, and non-flowable semisolid hydrogels after being placed at a temperature of 34 to 42 ℃ for 30 minutes.
In addition, the compositions provided by the above embodiments 1 to 9 of the present invention have gel time within the range of 0.5 to 10min measured at the temperature of 34 to 42 ℃ (measured at 34 ℃, 36 ℃, 39 ℃ and 42 ℃, respectively); the compositions have a de-coagulation time of 5-30 min when measured at a temperature of 5-32 deg.C (measured at 5 deg.C, 10 deg.C, 15 deg.C, 32 deg.C, respectively). It can be seen that the compositions provided in examples 1 to 9 of the present invention have good gelation-decondensation properties.
In addition, the compositions provided in examples 1 to 9 of the present invention have an RSD in the range of 0.26 to 0.44% in the day and an RSD in the range of 0.41 to 0.83% in the day. When water was measured as described above, the same spray pump was used to fill with water for injection, with an intra-day RSD of 0.36% and an inter-day RSD of 0.47%. These results indicate that the pharmaceutical compositions of the present invention, even after they undergo high temperature gelation-low temperature decondensation, have excellent uniformity of administration upon administration.
Example 11: preparation of pharmaceutical composition
With reference to the formulation and the preparation method of examples 1 to 8 (in reference to examples 6 to 8, all the processes were carried out according to the formulation and the preparation method of example 1), except that glycine was not added, the gel time (t1, 36 ℃) of the obtained 8 liquid pharmaceutical compositions was 32 to 85min, and the de-coagulation time (t2, 20 ℃) was 7.7 to 15 hours; the daily RSD is 1.63-2.56%, and the daytime RSD is 3.37-6.81%. This indicates that when glycine is not added, the composition takes more than 32min to gel at a temperature close to physiological body temperature of 36 ℃, which is very easy to cause drug loss and cannot accurately administer the drug for spray administration; in addition, the medicine can be placed for more than 7.7 hours at room temperature, namely 20 ℃, so that the medicine can be placed for a long time to be decondensed when the medicine needs to be administered after occasionally meeting high temperature, and the medicine can be nasally administered through spraying after the medicine is decondensed. In addition, the precision of dosing without the addition of glycine is unacceptable in terms of the precision of dosing characterized by intra-day RSD and inter-day RSD.
Example 12: preparation of pharmaceutical composition
Glycine used in the present invention is a polar uncharged amino acid, and a typical polar uncharged amino acid such as serine is similar thereto. In addition, a typical amino acid of a polar positively charged amino acid (i.e., a basic amino acid) is lysine, and a typical amino acid of a polar negatively charged amino acid (i.e., an acidic amino acid) is glutamic acid. Wherein serine and glycine are the closest in the aspects of amino acid physical and chemical properties such as isoelectric points and the like. For example, the physicochemical parameters of certain typical amino acids are as follows:
with reference to the formulation and the preparation method of examples 1 to 8 (in reference to examples 6 to 8, all the examples were carried out according to the formulation and the preparation method of example 1), except that glycine was replaced with the same amount of serine, lysine, or glutamic acid, the gel time (t1, 36 ℃) of the 24 liquid pharmaceutical compositions was 24 to 87min, and the decondensation time (t2, 20 ℃) was 6.2 to 17 hours; the daily RSD is 1.42-2.63%, and the daytime RSD is 2.76-8.32%. This indicates that when other amino acids (even serine with very similar properties) are used, the composition will gel more than 24min at a temperature close to physiological body temperature of 36 ℃, which is very easy to cause drug loss and cannot be accurately administered for spray administration; in addition, the medicine can be placed for more than 6.2 hours at room temperature, namely 20 ℃, so that the medicine can be placed for a long time to be decondensed when the medicine needs to be administered after occasionally meeting high temperature, and the medicine can be nasally administered through spraying after the medicine is decondensed. In addition, the precision of dosing with other amino acids is unacceptable in terms of the precision of dosing characterized by intra-day RSD and inter-day RSD.
Example 13: preparation of pharmaceutical composition
Referring to the formulation and the preparation method of examples 1 to 8 (in reference to examples 6 to 8, all the processes were performed according to the formulation and the preparation method of example 1), except that the organic acid was replaced with the same amount of acetic acid or lactic acid or no organic acid was added, the gel time (t1, 36 ℃) of the 24 liquid pharmaceutical compositions was 26 to 74min, and the decondensation time (t2, 20 ℃) was 6.4 to 12 hours; the daily RSD is 1.26-2.17%, and the daytime RSD is 2.54-5.63%. This shows that when citric acid or tartaric acid is not used, the composition needs more than 26min to gel at a temperature close to the physiological body temperature of 36 ℃, which is very easy to cause drug loss and cannot accurately administer the drug by spraying; in addition, the medicine can be placed for more than 6.4 hours at room temperature, namely 20 ℃, so that the medicine can be placed for a long time to be decondensed when the medicine needs to be administered after occasionally meeting high temperature, and the medicine can be nasally administered through spraying after the medicine is decondensed. In addition, the precision of dosing with other organic acids is unacceptable in terms of the precision of dosing characterized by intra-day RSD and inter-day RSD.
Example 14: providing a pharmaceutical composition
Risperidone oral solution is purchased from the market, and the specification of the risperidone oral solution is 30ml:30mg, and the Chinese medicine standard character H20065005. The gel time and the desolidinone oral solution (transferred to the vial of the spray pump used in the present invention) and the day RSD and day RSD were measured according to the method of the present invention. As a result, the daily RSD and the daytime RSD are both less than 1%, and gelation and de-gelation do not occur. When the risperidone oral solution is administrated through the nose, liquid medicine is easy to run off after spraying, so that the administration dosage is inaccurate.
Five preparations were prepared according to the formulations and methods of examples 1 to 5 of CN104398474a, and all of these preparations were gel-like substances, and were not changed in gel state after standing at both temperatures of 10 ℃ and 36 ℃ for 24 hours, and thus were not nasally administered by spraying.
Claims (19)
1. A pharmaceutical composition in liquid form comprising per 100 ml: 0.05-2.5 g of antipsychotic drug, 0.2-2 g of chitose, 1-5 g of sodium glycerophosphate, 0.5-1.5 g of organic acid, 0.2-1 g of glycine, 2-5 ml of ethanol, 0-0.5 g of optional bacteriostatic agent and water in balance; the antipsychotic agent is selected from: risperidone, olanzapine, aripiprazole; the organic acid is citric acid and/or tartaric acid.
2. The pharmaceutical composition according to claim 1, wherein the bacteriostatic agent is selected from the group consisting of: chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methylparaben, ethylparaben, propylparaben, butylparaben, and combinations thereof.
3. The pharmaceutical composition according to claim 1, comprising per 100 ml: 0.05-2 g of antipsychotic drug, 0.2-1 g of chitose, 1-2.5 g of sodium glycerophosphate, 0.5-1 g of organic acid, 0.2-1 g of glycine, 2-4 ml of ethanol, 0.005-0.5 g of bacteriostatic agent and water in balance.
4. The pharmaceutical composition according to claim 1, which is a flowable liquid after 1 hour at a temperature of less than or equal to 32 ℃.
5. The pharmaceutical composition according to claim 1, which is a flowable liquid after 1 hour at a temperature of 5 to 32 ℃.
6. The pharmaceutical composition according to claim 1, which is a non-flowable semi-solid hydrogel after 30min at a temperature higher than or equal to 34 ℃.
7. The pharmaceutical composition according to claim 1, which is a non-flowable semi-solid hydrogel after 30min at a temperature of 34-42 ℃.
8. The pharmaceutical composition according to claim 1, which has a gel time of 0.5 to 10min at a temperature of 34 to 42 ℃.
9. The pharmaceutical composition according to claim 1, which has a gel time of 0.5 to 2min at a temperature of 34 to 42 ℃.
10. The pharmaceutical composition according to claim 1, which has a decondensation time of 5-30 min at a temperature of 5-32 ℃.
11. The pharmaceutical composition according to claim 1, which has a decondensation time of 5-15 min at a temperature of 5-32 ℃.
12. The pharmaceutical composition according to claim 1, which is filled in a vial equipped with a spray pump.
13. The pharmaceutical composition according to claim 1, having a formulation as described in any one of the following EX1 to EX 5:
EX 1: 0.5g of active ingredients, 0.5g of chitose, 2g of sodium glycerophosphate, 0.75g of citric acid, 0.5g of glycine, 3ml of ethanol and a proper amount of water added to 100 ml;
EX 2: 0.05g of active ingredients, 0.2g of chitose, 1g of sodium glycerophosphate, 0.5g of citric acid, 0.2g of glycine, 2ml of ethanol and a proper amount of water added to 100 ml;
EX 3: 2g of active ingredients, 1g of chitose, 2.5g of sodium glycerophosphate, 1.5g of citric acid, 1g of glycine, 5ml of ethanol and a proper amount of water added to 100 ml;
EX 4: 2.5g of active ingredients, 2g of chitose, 5g of sodium glycerophosphate, 1g of citric acid, 0.75g of glycine, 4ml of ethanol and a proper amount of water added to 100 ml;
EX 5: 1g of active ingredients, 1.5g of chitose, 2g of sodium glycerophosphate, 0.8g of citric acid, 0.5g of glycine, 3ml of ethanol and a proper amount of water added to 100 ml;
wherein the active ingredient is risperidone, olanzapine or aripiprazole.
14. The pharmaceutical composition according to claim 1, having a formulation as described in any one of the following EX81 to EX 85:
EX 81: 0.5g of risperidone, 0.5g of chitose, 2g of sodium glycerophosphate, 0.75g of tartaric acid, 0.5g of glycine, 3ml of ethanol and a proper amount of water added to 100 ml;
EX 82: 0.05g of risperidone, 0.2g of chitose, 1g of sodium glycerophosphate, 0.5g of tartaric acid, 0.2g of glycine, 2ml of ethanol and a proper amount of water added to 100 ml;
EX 83: 2g of risperidone, 1g of chitose, 2.5g of sodium glycerophosphate, 1.5g of tartaric acid, 1g of glycine, 5ml of ethanol and a proper amount of water added to 100 ml;
EX 84: 2.5g of risperidone, 2g of chitose, 5g of sodium glycerophosphate, 1g of tartaric acid, 0.75g of glycine, 4ml of ethanol and a proper amount of water added to 100 ml;
EX 85: 1g of risperidone, 1.5g of chitose, 2g of sodium glycerophosphate, 0.8g of tartaric acid, 0.5g of glycine, 3ml of ethanol and a proper amount of water added to 100 ml.
15. A pharmaceutical composition according to any one of claims 1 to 14, which is prepared by a process comprising the steps of:
a) dissolving chitose, organic acid and glycine with sufficient water to obtain solution;
b) suspending the antipsychotic drug in ethanol, slowly adding into the solution obtained in the previous step, stirring for dissolving, sterilizing under hot pressure, and cooling in ice water bath for at least 30 min;
c) dissolving sodium glycerophosphate and an optional bacteriostatic agent in a proper amount of water for injection to prepare a solution containing 30-40% of sodium glycerophosphate, filtering the solution through a 0.22 mu m filter membrane for sterilization, and cooling the solution in an ice-water bath for at least 30min for later use;
d) slowly adding the solution obtained in the step c) into the solution obtained in the step b) in an ice bath under stirring, adding water to full amount, and fully stirring and mixing to obtain the pharmaceutical composition in a liquid form, wherein the pharmaceutical composition is optionally further filled into a medicine bottle provided with a spray pump.
16. A process for preparing a pharmaceutical composition according to any one of claims 1 to 14, comprising the steps of:
a) dissolving chitose, organic acid and glycine with sufficient water to obtain solution;
b) suspending the antipsychotic drug in ethanol, slowly adding into the solution obtained in the previous step, stirring for dissolving, sterilizing under hot pressure, and cooling in ice water bath for at least 30 min;
c) dissolving sodium glycerophosphate and an optional bacteriostatic agent in a proper amount of water for injection to prepare a solution containing 30-40% of sodium glycerophosphate, filtering the solution through a 0.22 mu m filter membrane for sterilization, and cooling the solution in an ice-water bath for at least 30min for later use;
d) slowly adding the solution obtained in the step c) into the solution obtained in the step b) in an ice bath under stirring, adding water to full amount, and fully stirring and mixing to obtain the pharmaceutical composition in a liquid form, wherein the pharmaceutical composition is optionally further filled into a medicine bottle provided with a spray pump.
17. Use of a pharmaceutical composition according to any one of claims 1-15 or a pharmaceutical composition prepared by a process according to claim 16 for the preparation of an antipsychotic agent.
18. Use according to claim 17, wherein the psychosis is schizophrenia.
19. Use according to claim 17, wherein the medicament is in the form of a formulation for nasal administration.
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