CN113368251A - Combined solvent and preparation method and application thereof - Google Patents
Combined solvent and preparation method and application thereof Download PDFInfo
- Publication number
- CN113368251A CN113368251A CN202110223021.XA CN202110223021A CN113368251A CN 113368251 A CN113368251 A CN 113368251A CN 202110223021 A CN202110223021 A CN 202110223021A CN 113368251 A CN113368251 A CN 113368251A
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- China
- Prior art keywords
- solvent
- water
- dmso
- drug
- liquid peg
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims description 8
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- 239000003814 drug Substances 0.000 claims abstract description 122
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000007788 liquid Substances 0.000 claims abstract description 35
- 239000000243 solution Substances 0.000 claims abstract description 28
- 238000011282 treatment Methods 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims description 87
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- 150000001875 compounds Chemical class 0.000 claims description 10
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- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
The present invention provides a combination solvent comprising: DMSO, liquid PEG, and water; the content of DMSO is 5% -10%, the content of liquid PEG is 65% -95%, the content of water is 0% -25%, and the percentage is the volume percentage of each component in the combined solvent. The invention also provides a medicinal solution containing the same and application thereof. The combined solvent is a neutral solvent, so that the combined solvent is safer than a strong acid (alkaline) solvent, and has no side effects such as stabbing pain, fester and the like; the oil solvent accounts for less proportion in the combined solvent, so that the pain feeling is reduced when the combined solvent is used for injection, the combined solvent is more suitable for injection, and the syringe is easier to extract and push during injection. When the medicine dissolved by the combined solvent is used for treatment, the curative effect of the medicine is not changed, and the absorption of the medicine is promoted to increase the curative effect of the medicine. In addition, the combined solvent disclosed by the invention does not need to be stored under the conditions of special pH and temperature, and is stable and easy to store.
Description
Technical Field
The invention relates to a combined solvent and a preparation method and application thereof, in particular to a combined solvent for dissolving water-insoluble medicines (such as nucleoside medicines) and a preparation method and application thereof.
Background
Many water-insoluble drugs exist in the prior art, and are generally prepared into tablets for oral use or are dissolved by using an oily solvent. The nucleoside drugs are important drugs for clinically treating virus infectious diseases, tumors and AIDS. Nearly 50% of the currently used antiviral drugs are nucleoside drugs, and the antitumor drugs Cytarabine (Cytarabine), Doxifluridine (Doxifluridine) and the like also belong to the nucleoside drugs. Most nucleoside drugs are practically insoluble in water, such as those disclosed in PCT patent application PCT/US 2018/022166: an azasaccharide-containing nucleoside analogue or a pharmaceutically acceptable salt thereof, wherein no solvent for the drug is specified. The medicine is an injection preparation, and needs to be dissolved in water to carry out subcutaneous injection on animals so as to achieve the curative effect; the drug solvent used by the applicant in the U.S. published article (Pedersen, n.c., Perron, m., Bannasch, m., Montgomery, e., Murakami, e., liennieks, m., & Liu, H. (2019) Efficacy and safety of the nucleic acid analogue GS-441524for the treatment of patients with natural soluble carboxylic acid impregnation properties. journal of Feline Medicine and Surgery) was a combination of 30% propylene glycol, 5% ethanol, 45% PEG400, 20% water, and the pH of the drug solution was adjusted to 1.5 with hydrochloric acid (since the drug is difficult to dissolve in water and organic solvents, it is necessary to lower the pH to facilitate its dissolution). However, it is known that highly acidic drug solvents are highly corrosive and when used for subcutaneous injection in cats, they inevitably cause many side effects such as stinging during and after injection, ulceration of the injection site (actually burning of the injection site by the strong acid), intolerance of the injected cats, withdrawal of the drug, and the like. In addition, the propylene glycol, ethanol and PEG400 used in the drug solvent are all oily solvents with high viscosity, and the oily solvents as injections have the following problems: 1) pain is caused by injection. Oily injection has no hydrosolvent to be easily absorbed after injection, and the injection part can be painful and is slowly absorbed after injection. For example, when a test tube is used for infants or when a female uses an ovulation promoting needle, the used reagent is an oily solvent, is very painful during injection, has lumps after injection and is not easy to absorb. 2) When the oily solvent is extracted with a syringe, it is not so easy to extract as it is with water. And when injected, the injection of the oily solvent is more difficult. 3) The cellular composition of all organisms is water rather than oil, so the proportion of oily solvent in a solvent is more unsafe.
Therefore, there is an urgent need for a solvent for dissolving water-insoluble drugs (e.g., nucleosides) that is safer, free of side effects such as stinging and ulceration, and that can be more easily withdrawn from a syringe and also more easily injected.
Disclosure of Invention
The invention aims to overcome the defects that in the prior art, water-insoluble drugs (such as nucleoside drugs) cannot be dissolved in neutral solvents such as water and the like, but only can be dissolved in strong acid (alkaline) or oily solvents, so that safety is reduced, side effects such as stabbing pain, ulceration of an injection part, intolerance and drug withdrawal are caused, the proportion of the oily solvents in the strong acid or alkaline solvents is high, so that injection pain is caused, a needle cylinder is not easy to extract, and the like. The combined solvent is a neutral solvent, so that the combined solvent is safer than a strong acid (alkaline) solvent, and has no side effects such as stabbing pain, fester and the like; and the oil solvent accounts for less proportion in the combined solvent, so that the pain feeling can be reduced when the combined solvent is used for injection, the combined solvent is more suitable for injection, and the syringe is easier to extract and push during injection. When the medicine dissolved by the combined solvent is used for treatment, the curative effect of the medicine is not changed, and the absorption of the medicine is promoted to increase the curative effect of the medicine. In addition, the combined solvent disclosed by the invention does not need to be stored under the conditions of special pH and temperature, and is stable and easy to store.
The solvents generally used in the art for dissolving water-insoluble drugs mainly include anhydrous ethanol, tween 40 and tween 80 or other strong acidic (alkaline) solvents, but these drugs have more or less difficulties of pain feeling during injection, difficulty in drawing and injecting, and slow absorption of the drugs. The present invention has been made in a large number of experiments and experiments, and it has been unexpectedly found that when a neutral solvent comprising DMSO (usually used only in the experimental stage) and liquid PEG (further comprising water) in a specific ratio is used, not only water-insoluble drugs (e.g., nucleoside drugs) can be dissolved, but also problems of strong pain feeling upon injection, difficulty in withdrawing and injecting a bolus, slow drug absorption, etc. are reduced when used for actual treatment; meanwhile, the curative effect of the medicine is not changed, the medicine absorption is promoted to increase the curative effect of the medicine, and the weak toxicity of DMSO has no influence on the final curative effect.
In order to solve the above technical problems, a first aspect of the present invention provides a combination solvent comprising: DMSO, liquid PEG (Polyethylene Glycol), and water; wherein, the content of DMSO is 5-10%, the content of liquid PEG is 65-95%, the content of water is 0-25%, and the percentage is the volume percentage of each component in the combined solvent.
Preferably, the liquid PEG is PEG200 (average relative molecular weight is generally 190-210), PEG400 (average relative molecular weight is generally 380-420) and/or PEG600 (average relative molecular weight is generally 570-630), such as PEG 400.
Preferably, the DMSO content may be 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9.9%, etc. The listed point values are exemplary only and not limiting. And it should be understood that the listed points can be freely combined, so that the concentration ranges formed by any combination are within the protection scope of the present invention. For example, 5% -6%, 5% -10%, 5% -7%, 5% -8%, 5% -9%, 6% -7%, 6% -8%, 6% -9%, 6% -10%, 7% -8%, 7% -9%, 7% -10%, 8% -9%, 8% -10%, etc. are within the scope of the present invention.
Preferably, the content of the liquid PEG may be 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, etc. The listed point values are exemplary only and not limiting. And it should be understood that the listed points can be freely combined, so that the concentration ranges formed by any combination are within the protection scope of the present invention. For example, 65% -70%, 65% -75%, 65% -80%, 65% -85%, 65% -90%, 70% -75%, 70% -80%, 70% -85%, 70% -90%, 70% -95%, 75% -80%, 75% -85%, 75% -90%, 75% -95%, 80% -85%, 80% -90%, 80% -95%, 85% -90%, 85% -95%, 90% -95% and the like are within the protection scope of the present invention.
Preferably, the water content is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, etc. The listed point values are exemplary only and not limiting. And it should be understood that the listed points can be freely combined, so that the concentration ranges formed by any combination are within the protection scope of the present invention. For example, it may be 0% -5%, 0% -10%, 0% -15%, 0% -20%, 5% -10%, 5% -15%, 5% -20%, 5% -25%, 10% -15%, 10% -20%, 10% -25%, 15% -20%, 15% -25%, 20% -25%, etc. all fall within the scope of the present invention.
In a preferred embodiment of the present invention, the combined solvent is DMSO 5% and liquid PEG 95%.
In a preferred embodiment of the present invention, the combined solvent is DMSO 5%, liquid PEG 70%, and water 25%;
in a preferred embodiment of the present invention, the combined solvent is DMSO 10% and liquid PEG 90%;
in a preferred embodiment of the present invention, the combined solvent is DMSO 10%, liquid PEG 65%, and water 25%;
in the present invention, the percentages are the volume percentages of the components in the entire combined solvent, unless otherwise specified.
Preferably, the pH of the combination solvent is 7.0 ± 0.5, such as 6.5, 6.6, 6.7, 6.9, 7.1, 7.2, 7.3, 7.4, 7.5, or the like.
Preferably, the combination solvent is a sterile combination solvent.
In the present invention, the solvents (e.g. DMSO, liquid PEG) mentioned generally refer to the solvents that are routinely used by those skilled in the art for performing experiments, and the solvents DMSO and liquid PEG used in the experiments are all chemical analysis pure (AR). For example, the DMSO purity is typically 99% or greater; the purity of the liquid PEG is generally more than 99%.
Preferably, the combination solvent is used for preparing a drug solution for subcutaneous injection; in particular, pharmaceutical solutions containing nucleoside agents against veterinary, e.g., feline or canine, coronavirus (e.g., feline infectious peritonitis or feline enteric coronavirus) are prepared.
In order to solve the above technical problems, the second aspect of the present invention provides a drug solution comprising the combination solvent according to the first aspect of the present invention and a water-insoluble drug.
Preferably, the water-insoluble drug is present in an amount generally greater than 15mg/ml, and may be 15mg/ml, 16mg/ml, 17mg/ml, 18mg/ml, 19mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 40mg/ml, 50mg/ml, 75mg/ml, 100mg/ml, and the like. The listed point values are exemplary only and not limiting. And it should be understood that the listed points can be freely combined, so that the concentration range of any combination is within the protection scope of the present invention, and for example, the concentration ranges of 15-25mg/ml, 15-50mg/ml, 15-75mg/ml, 15-100mg/ml, 25-50mg/ml, 50-75mg/ml, 50-100mg/ml and the like are within the protection scope of the present invention.
Preferably, the pH of the combination solvent is 7.0 ± 0.5, such as 6.5, 6.6, 6.7, 6.9, 7.1, 7.2, 7.3, 7.4, 7.5, or the like.
Preferably, the drug solution is a sterile drug solution.
Preferably, the purity of the water-insoluble drug is 98% or more.
Preferably, the pharmaceutical solution is for subcutaneous injection.
Preferably, the water-insoluble drug is a nucleoside drug, preferably a nucleoside antiviral drug, more preferably a nucleoside drug against a veterinary coronavirus (e.g., feline coronavirus or canine (e.g., dog) coronavirus), or a nucleoside drug for treating a disease caused by a veterinary coronavirus, preferably a feline coronavirus or canine (e.g., dog) canine coronavirus, more preferably a Feline Enteric Coronavirus (FECV). The disease caused by the veterinary coronavirus is preferably Feline Infectious Peritonitis (FIPV). In the present invention, the diseases caused by the veterinary coronavirus also generally include some derived diseases caused by the veterinary coronavirus. Furthermore, there are also some viral carriers that do not present these diseases or derived conditions, and nucleoside drugs against these viruses are of course within the scope of the present invention.
In a preferred embodiment of the present invention, the nucleoside antiviral drug is a azasugar-containing nucleoside analogue or a pharmaceutically acceptable salt thereof.
In a preferred embodiment of the present invention, the azasugar-containing nucleoside analogue may be a compound as listed in PCT/US2018/022166, for example one or more selected from the group consisting of:
In the present invention, the expression "one or more selected from … …" includes the combinations of the listed compounds. In certain embodiments of the invention, two or more compounds are used in combination to provide a greater therapeutic effect.
Preferably, the pharmaceutical solution may also contain other pharmaceutical excipients conventional in the art.
The dosage level at which the pharmaceutical solution of the invention is administered may be adjusted depending on the amount of the composition to achieve a desired diagnostic or therapeutic result, and may be, for example, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, and the like. The administration regimen may also be a single injection or multiple injections, or adjusted. The selected dose level and regimen will be reasonably adjusted depending on various factors including the activity and stability (i.e., half-life) of the drug solution, the formulation, the route of administration, combination with other drugs or treatments, the disease or condition to be detected and/or treated, and the health and prior medical history of the subject to be treated.
In order to solve the above technical problems, a third aspect of the present invention provides a method for preparing a pharmaceutical solution according to the second aspect of the present invention, comprising the steps of:
(1) mixing DMSO and water insoluble drug (generally, the drug is dissolved completely, the mixed solution is clear and transparent),
(2) liquid PEG and water were added sequentially.
Preferably, the DMSO is added to the water-insoluble drug and mixed well.
Preferably, the uniformly mixing is performed until a mixed solution of the water-insoluble drug and the DMSO is clarified.
In a preferred embodiment of the present invention, DMSO is first added to the drug (e.g., DMSO is poured onto the drug powder to dissolve the drug powder), mixed well (typically, the drug is completely dissolved, and the mixed solution is clear and transparent), then PEG400 is added (typically, the solution is also clear and transparent), and then water is added. The inventor finds in experiments that generally, the drug is fully mixed until the drug is dissolved to be clear and transparent, otherwise, the dissolution fails.
In order to solve the above technical problem, the fourth aspect of the present invention provides the use of the combination solvent according to the first aspect of the present invention for dissolving the water-insoluble drug according to the second aspect of the present invention (e.g. a drug for treating pets such as cats and dogs, especially for treating infectious peritonitis or feline enteric coronavirus and the like in cats).
In order to solve the above technical problem, a fifth aspect of the present invention provides a use of the combination solvent according to the first aspect of the present invention for preparing a pharmaceutical solution (e.g. veterinary injection) according to the second aspect of the present invention.
In order to solve the above technical problem, the present invention also provides a use of a pharmaceutical solution according to the second aspect of the present invention for the anti-viral, preferably coronavirus, more preferably a veterinary coronavirus (e.g. feline coronavirus or canine (dog) coronavirus) or for the treatment of a disease caused by a viral, preferably coronavirus, more preferably a veterinary coronavirus; preferably in the treatment of Feline Infectious Peritonitis (FIPV) or Feline Enteric Coronavirus (FECV).
In order to solve the above technical problem, the present invention also provides a method for combating viruses, preferably coronaviruses, more preferably veterinary coronaviruses, such as feline coronaviruses or canine (dog) coronaviruses, or for treating diseases caused by viruses, preferably coronaviruses, more preferably veterinary coronaviruses, comprising the use of a therapeutically effective amount of a pharmaceutical solution according to the second aspect of the present invention. The veterinary coronavirus resisting or treating diseases caused by the veterinary coronavirus is preferably Feline Infectious Peritonitis (FIPV) or Feline Enterocoronavirus (FECV).
In order to solve the above technical problem, the present invention also provides a method for treating a virus-induced disease by administering a pharmaceutical solution according to the second aspect of the present invention to an animal suffering from a virus-induced disease, comprising administering a therapeutically effective amount of a pharmaceutical solution according to the second aspect of the present invention. The virus is preferably a coronavirus, more preferably a veterinary coronavirus (e.g. a feline coronavirus or a canine (dog) coronavirus). The virus-induced disease is preferably Feline Infectious Peritonitis (FIPV) or Feline Enteric Coronavirus (FECV).
In the present invention, when the combined solvent is used to dissolve the drug to prepare a drug solution, the drug solution may be prepared in the form of a pharmaceutical preparation; that is, the present invention encompasses the provision of a pharmaceutical formulation comprising a combination solvent according to the first aspect of the present invention and a water-insoluble drug according to the second aspect of the present invention.
In the present invention, the term "comprising" has sometimes the same meaning as "consisting of … …". For example, "the combination solvent includes: DMSO, liquid PEG (Polyethylene Glycol), and water "also encompass the following, namely" the combined solvent consists of: DMSO, liquid PEG (Polyethylene Glycol), and water.
In order to solve the technical problems, the invention also provides a combined solvent, wherein the combined solvent consists of DMSO, liquid PEG and water; wherein, the content of DMSO is 5-10%, the content of liquid PEG is 65-95%, the content of water is 0-25%, and the percentage is the volume percentage of each component in the combined solvent.
Preferably, the DMSO, liquid PEG and/or water are as described in the first aspect of the invention.
In order to solve the above technical problems, the present invention also provides a drug solution consisting of the combination solvent according to the first aspect of the present invention and a water-insoluble drug.
The inventor finds that the drug can not be completely dissolved when the proportion of DMSO, liquid PEG or water is not in the range defined by the invention in the experimental process, and further, the inventor finds that the DMSO is higher than the range defined by the invention in the experimental process, the cell growth can be inhibited, and the toxicity is higher.
In the present invention, the water is generally sterile water (or sterile water for injection) which is conventionally used in the field at the time of the experiment.
In the present invention, the term "liquid PEG" generally refers to PEG in a liquid state, and generally refers to PEG having an average relative molecular weight of 1000 or less, which is distinguished from solid PEG. The PEG in different liquid states has different viscosity, different oiliness and different solubility; such as PEG200 (average relative molecular weight is generally 190-210), the viscosity is low, so the proportion to be added needs to be slightly higher, and the water ratio is reduced. PEG800 (average relative molecular weight generally 570-630) has relatively high viscosity and slightly high oiliness, so the proportion of the PEG added needs to be slightly reduced correspondingly.
In the present invention, the "oily solvent" is mainly distinguished from the aqueous solvent, and generally refers to a water-insoluble organic solvent or oil as a solvent. The solvent can be a solvent with higher viscosity (viscosity), and the addition of the solvent to the solution can increase the viscosity of the solution, and the solvents such as propylene glycol, ethanol, PEG400 and the like belong to oily solvents.
The term "pharmaceutically acceptable" means that the salts, solvents, excipients, etc., are generally non-toxic, safe, and suitable for use by the patient. The "patient" is preferably a mammal, more preferably a human.
The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19(1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camile G.Wermuth, ed., Wiley-VCH, 2002).
The "plurality" of the term "one or more" may refer to 2, 3, 4, 5, 6, 7, 8, or 9.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
1. the combined solvent is a neutral solvent; is safer than strong acid or strong alkaline injection solvent, and has no side effects such as stabbing pain, fester and the like.
2. The combined solvent is a neutral solvent, and meanwhile, the proportion of the oily solvent is small; when the medicine is used for dissolving medicines and then is injected into patients, the syringe is easier to extract and push; meanwhile, the less oily solvent is used, so that the pain feeling during injection is reduced.
3. The solvent of the invention can not only dissolve the medicine smoothly, but also not change the curative effect of the medicine, and can promote the diffusion and absorption of the medicine to increase the curative effect of the medicine, and the clinical curative effect is superior to that of domestic and foreign patents and documents.
4. The combined solvent disclosed by the invention does not need to be stored under the conditions of special pH and temperature, and is stable and easy to store.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
1) The drug information used in the following examples is as follows:
the medicine GS441524 (CAS NO.1355149-45-9) used in the invention is synthesized by the medicine Mingkude, and the purity is more than or equal to 98%.
2) The reagent information used in the following examples is shown in table 1 below:
TABLE 1
| Reagent | Commercial source and goods number | Purity of |
| DMSO | TIANJIN HENGXING CHEMICAL REAGENT Co.,Ltd. | Analytical purity |
| PEG400 | Taya-Tay Co Ltd, tin-free City | Analytical purity |
| Anhydrous ethanol | ANHUI ANTE FOOD Co.,Ltd. | Analytical purity |
Example 1
1. Preparing a medicine solution:
a. before the solvent is prepared, all experimental materials and reagents of solvent components are subjected to high-temperature sterilization treatment (because an antiviral medicament for treating feline infectious peritonitis needs subcutaneous injection to achieve the maximum bioavailability and the fastest effect, the aseptic treatment is an essential step);
b. the dry powder of the medicine GS441524 is dissolved in a solvent (the formula of the solvent is shown in the following table 2), and the solution can be stored and injected at normal temperature after the medicine is completely dissolved;
c. the dissolved solution is placed in the temperature range of-20 ℃ to 80 ℃, no medicine is separated out, and the medicine state is stable (see the following table 2 for details);
d. the concentration of the medicine in the solution after dissolution is more than or equal to 15 mg/ml.
Wherein, the preparation steps of the solvent comprise: adding DMSO into GS441524 powder (spraying DMSO onto the powder to dissolve the drug), mixing, adding PEG400 after the drug is completely dissolved and the solution is clear and transparent, and adding water after the solution is clear and transparent.
TABLE 2
The percentage is the volume percentage of each component in the whole solvent.
2. Administration of drugs
The number of cats with feline infectious peritonitis diagnosed in this example was 37-38 in the clinical validation experiment. Wherein, for the sick cats with pleural effusion and ascites, the diagnosis is confirmed by the conventional pleural effusion or ascites PCR result in the field, the SAA value shows the infection state, and the albumin/globulin ratio assists the diagnosis; for cats with no pleural fluid or ascites, the diagnosis is concluded from the positive results of the Livantat test, the SAA value indicating the infection status, exclusion of liver and kidney disease and toxic symptoms, and the albumin/globulin ratio, which are conventional in the art.
The drug GS441524 was completely dissolved according to the procedure of example 1 above, and then subcutaneously injected into the infected cats (treatment was performed by once daily injection at 5mg/kg, based on the kg body weight of the affected cats). Then observing and following all cats receiving the injection, and further detecting detection indexes of 37-38 cases of cats suffering from the disease, detection indexes in treatment (index for 2-3 days of medication, index for 7 days of medication, index for 30 days of medication, index for 6 weeks of medication, index for 8 weeks of medication), and detection indexes of drug withdrawal; the detection indexes mainly comprise: diagnosis and index guidance indexes related to the cat infectious neoperitonitis, such as age, weight, PCR diagnosis result, biochemical detection index, albumin/globulin value and the like of the cat. The results are shown in tables 3-9 below, where tables 4-9 show only the detailed data for treatment using the formulation of Table 3 with the maximum proportion of water in the 5% DMSO formulation, and additional data for cats treated by other means and then the formulation of this example are not shown in detail, but the final treatment is desirable for these cats.
TABLE 3
TABLE 4
TABLE 5
TABLE 6
TABLE 7
TABLE 8
TABLE 9
From the above data it can be seen that:
age and weight description of the group-entry cat: the weight of the patient is 2.4kg-5.5kg in 4-62 months and all the patients are at different ages.
Disease description in group-entry cats:
infectious peritonitis in cats is exudative in 80% and non-exudative in 20%. In exudative cats, 40% of the pleural fluid exudes and 60% of the ascites exudes. The exudative cat suffering from the diseases is affected by pleural effusion and ascites, and has the clinical manifestations of oppressed respiration and unsmooth respiration.
Because feline infectious peritonitis belongs to acute and malignant viral infection, the symptoms of fever, poor mental state, poor appetite and the like are commonly seen in sick cats.
Laboratory examination revealed elevated blood leukocytes, with insignificant changes in about 20% of cats with elevated blood leukocytes, but significant inflammation was suggested by SAA values. Because of the consumption of albumin by the body in disease, biochemical examination has shown that the albumin/globulin ratio is significantly lower than 0.5 in about 95% of the affected cats. In addition, due to the invasion of the virus to the liver and kidney of the cat, about 5 percent of the cats have abnormal kidney index values and about 24 percent of the cats have abnormal liver index values in biochemical examination.
The group data presented were all combination treatments without other drugs, but were only single-drug treatments with the solvent ratio dissolved GS441524 of the present application.
The treatment results are as follows:
follow-up treatment results show that:
after the medicine is taken for 2-3 days, about 76% of the sick cats have the temperature drop and the fever symptom is eliminated;
after 1 week of administration, about 88% of exudative cats can absorb hydrothorax and ascites, and eliminate respiratory symptom;
after 4 weeks of administration, about 100% of all laboratory indications in the affected cats returned to normal.
Stopping treatment in about 29% of the affected cats for 1 month; stopping treatment for about 57% of the affected cats for 1.5 months; about 14% of the affected cats were dosed for 2 months and treatment was discontinued. After all cats had stopped treatment, no disease recurred after 1 year of follow-up. After 3 cats with the disease stop treating for half a year, invasive sterilization operation is carried out, and no disease recurrence is found.
The detection indexes of the sick cat and the laboratory are as follows:
the body temperature range (anal temperature) of healthy cats is 37.5-39.5 ℃ for young cats and 38-39 ℃ for adult cats.
Blood term test, leukocyte normal range: 5.50-19.50
SAA is checked, and SAA is less than or equal to 2.00mg/L and normal; 2.00-10.00mg/L is higher; more than 10.00mg/L of obvious inflammation
According to the above results, it can be seen that the drug, when dissolved in the solvent described in example 1, has a curative effect on both permeable infectious peritonitis (pleural effusion or ascites during disease) and impermeable infectious peritonitis (pleural effusion or ascites during disease), and has no side effects such as stinging and ulceration. When the medicine is used for dissolving the medicine and then is injected into the sick cat, the syringe is easier to extract and push; meanwhile, the pain feeling during injection can be reduced, and the medicine is quickly absorbed after injection. And DMSO is controlled within the range, the weak toxicity of DMSO does not influence the exertion of the drug effect, and the DMSO is in a safe range.
In addition, after the medicine is dissolved in the solvent with the pH value of 7.0 in the embodiment 1, the clinical curative effect of the medicine is not affected, and meanwhile, the solvent provided by the invention has the effect of helping the medicine to diffuse and absorb (because DMSO is a transdermal enhancer), the medicine has faster effect and better clinical curative effect, and no injection pain or intolerance case exists. It can be seen from the table that the formulation of this example provides excellent therapeutic effect in a short time (shorter than the prior art reports).
Comparative example 1
1. The formulation method of example 1 was followed using other common solvents, and the results are shown in Table 4 below. As can be seen from the table, the following commonly used solvents, particularly solvents commonly used for dissolving water-insoluble drugs (e.g., Tween 40, Tween 80), all have various disadvantages.
TABLE 4
2. The solvent was prepared according to the procedure described in example 1, and the formulation and results are shown in table 5 below. It can be seen that the proportion of water in the solvent is too high, and the proportion of DMSO or PEG400 is too high or too low, and the resulting solvent cannot completely dissolve the drug GS 441524.
TABLE 5
Comparative example 2
After 5% DMSO dissolves the drug, propylene glycol, absolute ethyl alcohol, Tween 80, Tween 40, alpha-cyclodextrin and beta-cyclodextrin in any proportion are used to replace PEG400 or water to prepare solutions, the solutions are respectively placed in an environment with the temperature of lower than 18.4 ℃,4 ℃ and-20 ℃ for 1 month, only the solvent of the application has no crystallization and precipitation, no freezing condition exists, and all other proportion solvents have freezing phenomena.
Claims (10)
1. A combination solvent, wherein the combination solvent comprises: DMSO, liquid PEG, and water; wherein, the content of DMSO is 5-10%, the content of liquid PEG is 65-95%, the content of water is 0-25%, and the percentage is the volume percentage of each component in the combined solvent.
2. The combination solvent of claim 1, wherein the liquid PEG is PEG200, PEG400 and/or PEG600, preferably PEG 400.
3. The combination solvent of claim 1 or 2, wherein the DMSO content is 6%, 7%, 8%, or 9%;
and/or, the liquid PEG content is 70% to 90%, such as 75%, 80% or 85%;
and/or the water content is 5%, 10%, 15% or 20%.
4. The combination solvent of any one of claims 1 to 3, wherein the combination solvent is DMSO 5% and liquid PEG 95%;
and/or, the combined solvent is DMSO 5%, liquid PEG 70%, and water 25%;
and/or, the combined solvent is DMSO 10% and liquid PEG 90%;
and/or, the combined solvent is DMSO 10%, liquid PEG 65% and water 25%;
the percentage is the volume percentage of each component in the combined solvent.
5. The combination solvent of any one of claims 1 to 4, wherein the combination solvent has a pH of 7.0 ± 0.5; and/or, the combination solvent is a sterile combination solvent; and/or the DMSO is chemically pure, preferably DMSO with the purity of more than 99 percent; and/or, the liquid PEG is chemically pure, preferably the liquid PEG with the purity of more than 99 percent; and/or, the combination solvent is used for preparing a drug solution for subcutaneous injection.
6. A drug solution comprising the combination solvent of any one of claims 1 to 5 and a water-insoluble drug;
preferably, the content of the water-insoluble drug is higher than 15 mg/ml; and/or the pH value of the medicine solution is 7.0 +/-0.5; and/or, the drug solution is a sterile drug solution; and/or the purity of the water-insoluble drug is more than 98%; and/or, the pharmaceutical solution is for subcutaneous injection.
7. The pharmaceutical solution according to claim 6, wherein the water-insoluble drug is a nucleoside drug, preferably a nucleoside antiviral drug, more preferably a nucleoside drug against a veterinary coronavirus, preferably a feline coronavirus or a canine coronavirus such as a feline enterocoronavirus, or a nucleoside drug for the treatment of a disease caused by a veterinary coronavirus, preferably feline infectious peritonitis;
preferably, the nucleoside antiviral drug is a nitrogen heterosaccharide nucleoside analogue or a pharmaceutically acceptable salt thereof; the azasugars-containing nucleoside analogs are preferably selected from one or more of the following compounds:
8. a process for the preparation of a pharmaceutical solution according to claim 6 or 7, characterized in that it comprises the following steps:
(1) mixing the DMSO and the water-insoluble drug uniformly,
(2) sequentially adding liquid PEG and water;
preferably, the DMSO is added into the water-insoluble drug and mixed evenly; and/or uniformly mixing until the mixed solution of the water-insoluble drug and the DMSO is clear.
9. Use of a combination solvent as defined in any one of claims 1 to 5 for dissolving a water-insoluble drug as defined in claim 6 or 7.
10. Use of a combination solvent as defined in any one of claims 1 to 5 in the preparation of a pharmaceutical solution as defined in claim 6 or 7.
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| WO2023207942A1 (en) * | 2022-04-25 | 2023-11-02 | 北京沐华生物科技有限责任公司 | Nucleoside drug for treating or preventing coronavirus infection, and use thereof |
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