CN110613726B - Application of nucleoside compound - Google Patents
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- CN110613726B CN110613726B CN201910912419.7A CN201910912419A CN110613726B CN 110613726 B CN110613726 B CN 110613726B CN 201910912419 A CN201910912419 A CN 201910912419A CN 110613726 B CN110613726 B CN 110613726B
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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
- A61K31/70—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
- A61P31/20—Antivirals for DNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22
Abstract
The invention relates to application of a nucleoside compound in preparing a medicine for treating cat stomatitis, a medicine and a preparation method thereof. The nucleoside compound has a structure represented by the following formula (1):
in the formula (I), R1Is a hydrogen atom or a group shown as the formula (a),
r in the formula (a)2Selected from the group consisting of alkanyl and cycloalkanyl groups having 1 to 8 carbon atoms. Researches show that the nucleoside compound with the structure shown in the formula (I) can be prepared into a medicament for treating the feline stomatitis. The application provides a new application of the nucleoside compound and a new medicine for treating the feline stomatitis. Researches show that the nucleoside compound has obvious drug effect on treating the feline stomatitis, has wide application prospect and has great popularization and application values.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to application of a nucleoside compound in preparing a medicine for treating feline stomatitis, a medicine and a preparation method thereof.
Background
Feline stomatitis is an inflammation occurring in a wide range in the oral cavity of a cat, and excludes inflammation of mucous membrane and loss of supporting tissue in the local area such as gingivitis and periodontal disease. Cat stomatitis is divided into two major categories: the inflammation range exceeds the gingival, and the inflammation is spread to the alveolar mucosa and even the lip mucosa and is the stomatitis; inflammation and pebble-bed hyperplasia exist in the back of the mouth, from the side of the oropharynx to the vicinity of the palatoglossal arch, which is called as caudal stomatitis, which is the most difficult to treat and most likely and most common stomatitis recurs.
Feline stomatitis is considered to be an inflammatory disease with unknown pathology, numerous participants and no lock. Of the media suspected of being associated with feline stomatitis over the years, only feline calicivirus has its association with bacteria, plaque, and the like. Previously suspected related feline aids, feline leukemia, feline herpes virus, hansenba systemic infection were all confirmed to be unrelated. In short, feline stomatitis does not reveal a clear pathogenic entity, and more likely, the body's immune system generates an excessive immune response to one or more mediators not known at present, resulting in inflammation.
At present, surgical treatment and drug treatment are mainly adopted for treating the cat stomatitis, tooth extraction is the most effective treatment method in the treatment of the cat stomatitis for many years, but the organ damage to the cat is obvious, and a great number of cats suffering from the stomatitis can not be cured and die even after tooth extraction. The prior medicament treatment generally uses glucocorticoid as a main component and is assisted by antibiotics and oral cavity cleaning. This is a life-long medication that suppresses the immune system from dominating inflammation, but eventually the hormones may lose their efficacy or produce undeniated side effects. The drug treatment can be an alternative when tooth extraction is impossible, or can be an innocent treatment when the operation is ineffective.
Therefore, the development of a drug with specific curative capacity for cat stomatitis can avoid tooth extraction of cats all over the mouth and does not produce side effects like hormone drugs, and the market has great demand for the drug.
Disclosure of Invention
Based on the above, a new application of the nucleoside compound is needed, and particularly, the application of the nucleoside compound in preparing a medicament for treating feline stomatitis is provided.
Accordingly, in one aspect of the invention, a medicament for treating stomatitis of cats is provided. Correspondingly, also provides a preparation method of the medicine.
In another aspect of the present invention, there is provided a use of a nucleoside compound in the preparation of a medicament for treating feline stomatitis, the nucleoside compound having a structure represented by the following formula (I):
r in the formula (a)2Is selected from alkane radical or cycloalkane radical with 1-8 carbon atoms.
Researches show that the nucleoside compound with the structure shown in the formula (I) can be prepared into a medicament for treating the feline stomatitis. The application provides a new application of the nucleoside compound and a new medicine for treating the feline stomatitis. Researches show that the nucleoside compound has obvious drug effect on treating the feline stomatitis, has wide application prospect and has great popularization and application values.
In one embodiment, the alkanyl group is selected from one of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and 2-ethyl-butyl, and the cycloalkaneyl group is cyclopentyl or cyclobutyl.
In one embodiment, the nucleoside compound is selected from one of the compounds having the structure shown below:
in one embodiment, the disease is feline stomatitis caused by feline calicivirus.
A medicine for treating cat stomatitis is mainly prepared from pharmaceutically acceptable auxiliary materials and a nucleoside compound which is used as an active ingredient and has a structure shown as the following formula (I);
wherein R is1Is a hydrogen atom or a group shown as the formula (a),
r in the formula (a)2Is selected from alkane radical or cycloalkane radical with 1-8 carbon atoms.
In one embodiment, the medicament is an injection or an oral formulation.
In one embodiment, the medicine is an injection, the auxiliary material comprises a solvent, and the solvent is at least one selected from water, polyethylene glycol with the average molecular weight of 200-600, propylene glycol, ethanol and isotonic sodium chloride solution;
in the injection, the content of the nucleoside compound is (5-20) mg/mL.
In one embodiment, the solvent comprises ethanol, polyethylene glycol and propylene glycol, and the volume ratio of the ethanol to the polyethylene glycol to the propylene glycol is (1.5-2.5): (4.5-5.5): (2.5-4).
In one embodiment, the medicament is an oral preparation, and the auxiliary materials comprise a filler, a binder, a disintegrant and a lubricant;
the medicine comprises, by weight, 1-50 parts of the nucleoside compound, 5-95 parts of a filler, 1-10 parts of an adhesive, 1-20 parts of a disintegrant and 0-5 parts of a lubricant.
The invention provides a preparation method of any one of the medicines for treating the stomatitis of cats, which comprises the following steps: mixing the nucleoside compound with the adjuvant.
Drawings
FIG. 1 is a graph of the dissolution profiles of oral tablets prepared in example 7 of the present invention in 4 different media.
Detailed Description
In order that the invention may be more fully understood, a more particular description of the invention will now be rendered by reference to specific embodiments thereof that are illustrated in the appended drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The researchers of the present invention found, through research, a nucleoside compound having a structure represented by the following formula (I);
in the formula (I), R1Is a hydrogen atom or a group shown as the formula (a),
r in the formula (a)2Is selected from alkane radical or cycloalkane radical with 1-8 carbon atoms.
The nucleoside compound with the structure shown in the formula (I) is prepared into a medicament which has the effect of treating the stomatitis of cats. The application provides a new application of the nucleoside compound and a new medicine for treating the feline stomatitis. Researches show that the nucleoside compound has obvious drug effect on treating the feline stomatitis, has wide application prospect and has great popularization and application values.
In one embodiment, the alkanyl group is selected from one of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and 2-ethyl-butyl, and the cycloalkaneyl group is cyclopentyl or cyclobutyl.
In one embodiment, the nucleoside compound is one selected from compounds having the structures represented by the following formulae (I-1) to (I-6):
further, the nucleoside compound is selected from one of the above-mentioned formula (I-3), formula (I-4), formula (I-5) and formula (I-6).
A medicine for treating cat stomatitis is mainly prepared from pharmaceutically acceptable auxiliary materials and a nucleoside compound which is used as an active ingredient and has a structure shown as the following formula (I);
wherein R is1Is a hydrogen atom or a group shown as the formula (a),
r in the formula (a)2Is selected from alkane radical or cycloalkane radical with 1-8 carbon atoms.
In one embodiment, the medicament is an injection and the excipient comprises a solvent.
Further, the solvent is at least one selected from water, polyethylene glycol (PEG) with the average molecular weight of 200-600, propylene glycol, ethanol and isotonic sodium chloride solution. In the injection, the content of the nucleoside compound is (5-20) mg/mL.
It will be appreciated that the injectable formulation is a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, and that the nucleoside compound may be dispersed uniformly in the solvent to form a solution, or the nucleoside compound may be formulated with an adjuvant such as PEG400 as a lyophilized powder.
In one embodiment, the solvent comprises ethanol, polyethylene glycol and propylene glycol, and the volume ratio of the ethanol to the polyethylene glycol to the propylene glycol is (1.5-2.5): (4.5-5.5): 2.5-4.
The solvent with the composition is adopted to interact with the nucleoside compound with the content, so that the solubility and the stability of the medicament can be improved, and the prepared injection has good treatment effect, is convenient to administer and operate and takes effect quickly.
Further, the injection comprises 1000mg of the nucleoside compound, 20 to 25mL of ethanol, 45 to 50mL of polyethylene glycol (PEG200, PEG300, PEG400 or PEG600) having an average molecular weight of 200 to 600, and 20 to 30mL of propylene glycol, in 100 mL.
In a specific example, the injection comprises 1000mg of the above nucleoside compound, 20mL of ethanol, 50mL of PEG400, and 30mL of propylene glycol in units of 100 mL.
Further, the effective dose of the above nucleoside compound as an active ingredient in the injection depends on the severity of the condition to be treated. Dosages of from about 0.01mg/kg to about 100mg/kg body weight per day are contemplated. Specifically, about 0.1mg/kg to about 10mg/kg body weight per day; for example, for a cat of about 4kg body weight, the daily candidate dose will be in the range of 0.4mg to 40mg, and may take the form of a single dose or multiple doses.
In one embodiment, the adjuvant further comprises a co-solvent selected from at least one of monoglycerides, diglycerides, and oleic acid.
In one embodiment, the medicament is an oral preparation, and the auxiliary materials comprise a filler, a binder, a disintegrant and a lubricant;
the medicine comprises, by weight, 1-50 parts of the nucleoside compound, 5-95 parts of a filler, 1-10 parts of an adhesive, 1-20 parts of a disintegrant and 0-5 parts of a lubricant.
In one embodiment, the medicine comprises, by weight, 5-20 parts of the nucleoside compound, 60-80 parts of a filler, 3-10 parts of a binder, 2-8 parts of a disintegrant and 1-3 parts of a lubricant.
In a specific embodiment, the oral preparation comprises 10 parts of the nucleoside compound, 76 parts of a filler, 5 parts of a binder, 7 parts of a disintegrant and 2 parts of a lubricant in parts by weight.
Further, the filler is selected from at least one of microcrystalline cellulose, calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; the binder is selected from at least one of povidone (PVP), starch, gelatin and acacia; the disintegrating agent is selected from at least one of low-substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium (CCMC-Na), corn starch and alginic acid, and the lubricant is selected from at least one of magnesium stearate, phosphatidic acid and talcum powder.
It will be appreciated that the oral dosage form may be in the form of tablets, dispersible powders or granules, and that the oral dosage form may also include flavoring agents, coloring agents, preservatives and the like to enhance palatability. The tablet may be coated or uncoated, for example, by coating with a material such as wax-containing glyceryl monostearate or glyceryl distearate, to delay disintegration and absorption of the drug in the gastrointestinal tract and provide sustained action.
In one embodiment, the nucleoside compound in the above-mentioned medicament is one selected from compounds having a structure shown below:
further, the nucleoside compound is selected from one of the above-mentioned formula (I-3), formula (I-4), formula (I-5) and formula (I-6).
The nucleoside compound with the structure shown in the formula (I) and auxiliary materials are prepared into the injection or oral preparation, and the injection or oral preparation has good drug effect on treating the cat stomatitis.
The invention provides a preparation method of any one of the medicines for treating the stomatitis of cats, which comprises the following steps: mixing the nucleoside compound with the structure shown in the formula (I) and auxiliary materials.
Further, the preparation method of the injection medicament comprises the following steps:
a nucleoside compound having a structure represented by the formula (I) is dissolved in a solvent to obtain an injection. The composition can be administered by subcutaneous injection, intramuscular injection, intravenous injection, etc.
Further, the preparation method of the oral preparation comprises the following steps:
mixing the nucleoside compound with structure shown in formula (I) with adjuvants (filler, binder, disintegrant, lubricant, etc.), granulating or tabletting, and making into tablet, powder or granule.
The preparation method of the injection or the oral preparation has simple process and can be completed by adopting the existing equipment.
The following are specific examples
EXAMPLE 1 preparation of Compound of formula (I-2)
The reaction formula is as follows:
the preparation process comprises the following steps: a round-bottomed flask was charged with 1.50g of the nucleoside compound of the formula (I-1), 200mL of tetrahydrofuran and 2.26g of the active phosphate ester of the formula (B), cooled to 0 ℃ in an ice bath, and 10mL of a t-butylmagnesium chloride solution (1.0M tetrahydrofuran solution) was slowly added dropwise with stirring, and after completion of the addition, the temperature was raised to 40 ℃ and the reaction was carried out at that temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrated solution was added to 200mL of dichloromethane, washed 2 times with 50mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography using a mixed solution of ethyl acetate/petroleum ether-2/1 as an eluent to obtain 0.82g of the compound of formula (I-2) in a calculated yield of 29%.
Process for producing the Compound of formula (I-2)1H NMR(400MHz,CD3OD):7.75(d,1H),7.24-7.13(m,2H),7.10-6.99(m,3H),6.86-6.72(m,2H),4.70(d,1H),4.38-4.23(m,2H),4.20(m,1H),4.09(m,,1H),4.05-3.90(m,2H),3.71(m,1H),1.16(dd,1H),1.13-1.06(m,5H).MS m/z＝547.4[M+1]。
EXAMPLE 2 preparation of the Compound of formula (I-3)
The reaction formula is as follows:
the preparation process comprises the following steps: a round-bottomed flask was charged with 1.50g of the nucleoside compound of the formula (I-1), 200mL of tetrahydrofuran and 2.33g of the activated phosphate ester of the formula (C), cooled to 0 ℃ in an ice bath, and 10mL of a t-butylmagnesium chloride solution (1.0M tetrahydrofuran solution) was slowly added dropwise with stirring, and after completion of the addition, the temperature was raised to 40 ℃ and the reaction was carried out at that temperature for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, the concentrated solution was added to 200mL of dichloromethane, washed 2 times with 50mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography using a mixed solution of ethyl acetate/petroleum ether (2/1) as an eluent to obtain 0.93g of a product with a calculated yield of 32%.
Process for producing the Compound of formula (I-3)1H NMR(400MHz,CD3OD):7.86(s,1H),7.33-7.25(m,2H),7.21-7.12(m,3H),6.91(d,1H),6.87(d,1H),4.93(m,1H),4.80(d,1H),4.44-4.34(m,1H),4.33-4.24(m,1H),4.18(t,1H),3.82(m,2H),1.27(dd,3H),1.18(dd,6H).MS m/z＝561.11[M+1]。
EXAMPLE 3 preparation of the Compound of formula (I-4)
The reaction formula is as follows:
the preparation process comprises the following steps: a round-bottomed flask was charged with 1.50g of the nucleoside compound of the formula (I-1), 200mL of tetrahydrofuran and 2.55g of the active phosphate ester of the formula (D), cooled to 0 ℃ in an ice bath, and 10mL of a t-butylmagnesium chloride solution (1.0M tetrahydrofuran solution) was slowly added dropwise with stirring, and after completion of the addition, the temperature was raised to 40 ℃ and the reaction was carried out at that temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrated solution was added to 200mL of dichloromethane, washed 2 times with 50mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography using a mixed solution of ethyl acetate/petroleum ether (2/1) as an eluent to obtain 1.04g of a product with a calculated yield of 33.5%.
Process for producing the Compound of formula (I-4)1H NMR(400MHz,CD3OD):8.06(s,1H),7.37(d,1H),7.30(t,2H),7.20-7.14(m,3H),7.12(d,1H),4.74(d,1H),4.49-4.39(m,2H),4.38-4.29(m,1H),4.17(t,1H),4.09-3.95(m,2H),3.94-3.80(m,1H),1.49(m,1H),1.34(m,4H),1.30(d,3H),0.88(t,6H).MS m/z:603.1[M+1]。
EXAMPLE 4 preparation of the Compound of formula (I-5)
The reaction formula is as follows:
the preparation process comprises the following steps: 1.50g of the nucleoside compound of the formula (I-1), 200mL of tetrahydrofuran and 2.40g of the active phosphate ester of the formula (E) were charged into a round-bottomed flask, cooled to 0 ℃ in an ice bath, 10mL of a t-butylmagnesium chloride solution (1.0M tetrahydrofuran solution) was slowly added dropwise with stirring, and after completion of the addition, the temperature was raised to 40 ℃ to react for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the concentrated solution was added to 200mL of dichloromethane, washed 2 times with 50mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography using a mixed solution of ethyl acetate/petroleum ether-1/1 as an eluent to give 1.42g of the compound of formula (I-5) in 48% yield.
Process for producing compound of formula (I-5)1H NMR(400MHz,CD3OD):7.86(m,1H),7.35-7.08(m,5H),6.94-6.85(m,2H),4.95-4.85(m,1H),4.79(m,1H),4.46-4.34(m,2H),4.34-4.24(m,1H),4.19(m,1H),3.82(m,1H),2.27(m,2H),2.01(m,2H),1.84-1.68(m,1H),1.62(m,1H),1.30-1.17(m,3H).MS m/z＝573.1[M+1]。
EXAMPLE 6 preparation of the Compound of formula (I-6)
The reaction formula is as follows:
the preparation process comprises the following steps: a round-bottomed flask was charged with 1.50g of the nucleoside compound of the formula (I-1), 200mL of tetrahydrofuran and 2.47g of the active phosphate ester of the formula (F), cooled to 0 ℃ in an ice bath, and 10mL of a t-butylmagnesium chloride solution (1.0M tetrahydrofuran solution) was slowly added dropwise with stirring, and after completion of the addition, the temperature was raised to 40 ℃ to react for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, the concentrated solution was added to 200mL of dichloromethane, washed 2 times with 50mL of saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated residue was separated by silica gel column chromatography using a mixed solution of ethyl acetate/petroleum ether-1/1 as an eluent to give 1.58g of the compound of formula (I-6) in a calculated yield of 52%.
Process for producing compound of formula (I-6)1H NMR(400MHz,CD3OD):7.86(s,1H),7.34-7.23(m,2H),7.15(m,3H),6.96-6.88(m,2H),5.14-5.00(m,1H),4.79(d,,1H),4.48-4.35(m,2H),4.31(m,1H),4.20(t,1H),3.78(m,1H),1.82(m,2H),1.75-1.50(m,6H),1.22(dd,3H).MS m/z＝587.1[M+1]。
Example 7 oral tablet formulation for treating feline stomatitis
The process is described as follows:
10.00 g of a compound shown in a formula (I-3), 38.00 g of microcrystalline cellulose, 38.00 g of lactose, 5.00 g of povidone (PVP for short), 5.00 g of low-substituted hydroxypropyl cellulose (L-HPC) and 5.00 g of croscarmellose sodium (CCMC-Na) are stirred uniformly, sieved by a 40-mesh sieve for 2 times and fully dispersed to form a premixed material, 2.00 g of magnesium stearate and the premixed material are weighed, stirred and uniformly mixed to form an intermediate material, and then the intermediate material is tabletted by a tabletting machine to prepare the oral tablet.
TABLE 1 oral tablet formulation
| Material(s) | Ratio (%) | Theoretical quantity (g) | Use of | Model number |
| Compound I-3 | 10.0％ | 10.00 | Main medicine | |
| Microcrystalline cellulose | 38.0％ | 38.00 | Filler | 102 |
| Lactose | 38.0％ | 38.00 | Filler | 30GR |
| PVP | 5.0％ | 5.00 | Adhesive agent | K-29/32 |
| L-HPC | 5.0％ | 5.00 | Disintegrating agent | SH-LH11 |
| CCMC-Na | 2.0％ | 2.00 | Disintegrating agent | ND-2HS |
| Magnesium stearate | 2.0％ | 2.00 | Lubricant agent | |
| Total up to | 100.0％ | 100.00 |
And (3) dissolution rate detection:
the dissolution of the prepared sample is used as an investigation index to research the dissolution of the tablet. The prepared samples were tested according to the examination method of disintegration time limit of 0921 and the measurement method of dissolution rate and release rate of 0931 in the 4 th part of the 2015 edition of the Chinese pharmacopoeia.
The dissolution method comprises the following steps: in the 2 nd method (paddle method), the rotation speed was 50rpm, the temperature was 37 ℃, the volume of the dissolution liquid was 900mL (the concentration of Sodium Dodecyl Sulfate (SDS) in the dissolution medium was 0.5%), and the sampling time points were set to 5min, 10min, 15min, 20min, 30min, and 45 min. The dissolution results for the samples are shown in table 2 below and figure 1.
Table 2 dissolution results of oral tablets in 4 media
EXAMPLE 8 efficacy test for the treatment of feline stomatitis
1. The preparation method of the test substance comprises the following steps:
1000mg of the nucleoside compound of the formula (I-3) was weighed, dissolved in a solvent mixed with 20mL of ethanol, 50mL of PEG400 and 30mL of propylene glycol, shaken well and dispensed into 20 vials of 5mL of penicillin, to prepare an injection preparation of the test compound.
In addition, a solution prepared by uniformly mixing 20mL of ethanol, 50mL of PEG400 and 30mL of propylene glycol is prepared and is subpackaged into 20 vials with 5mL serving as a solvent injection.
2. Screening of the test disease cats:
the number of sick cats selected in the trial was 20.
The screening standard meets the following 1-5 conditions: 1, positive PCR detection of the calicivirus (the calicivirus is closely related to stomatitis), negative detection of the herpes virus (stomatitis caused by the herpes virus is self-limiting), and elimination of stomatitis caused by the herpes virus; 2, continuously salivating in large quantity; 3, ulcer or pustule appears on the surface of the tongue or the oral cavity, and redness and swelling or bleeding appear on the gingiva; 4, fever symptoms exist in the early stage; 5, there is no more voluntary food intake, emaciation, and listlessness.
3. Administration and observation:
randomly dividing 20 sick CATs into 2 groups, wherein each group comprises 10 CATs with the numbers of CAT1, CAT2, CAT3 to CAT 20; injecting tested drugs (CAT 1-CAT 10) once a day with the dosage of 3 mg/kg; the other control group was washed with 2mL of silver ion lotion (a drug currently used for stomatitis) per day to kill oral bacteria and viruses and injected with vehicle (CAT 11-CAT 20).
The salivation, oral cavity recovery and mental condition of each cat were observed and recorded daily for 14 days.
4. The observation records and inspection results are shown in the following tables 3-5:
TABLE 3 drooling of sick cats
Note: "+ + + + + + + +", "+" indicate severity; wherein the more "+" the more severe; "-" indicates no more drooling.
TABLE 4 oral restoration of sick cats
Note: the severity of ulcerated, pustular or gingival bleeding in the mouth is indicated by "+ + + +", "+ + + + +", "+", respectively; wherein the more "+" the more severe; "-" represents substantial recovery.
From the examination results of the administration group and the placebo group in the above tables 3-5, it can be seen that the salivation condition of the administration group is greatly reduced after 3 days of administration, no salivation condition is found on the tenth day, the administration group is almost recovered to the normal cat state after 2 weeks of treatment under the condition of oral healing, and a little gum is reddish except for part of cats due to the existence of dental calculus. The silver ion lotion has the function of killing bacteria and viruses, and the silver ion lotion is applied to the control group, but the sialorrhea and ulcer of the stomatitis cats of the control group are hardly improved, and the situation is partially worsened. In summary, the drug provided by the invention has significant curative effect compared with a control group.
The compounds of the above formula (I-1), formula (I-2), formula (I-4), formula (I-5) and formula (I-6) were also tested in accordance with the procedures of examples 7 and 8, respectively, and the prepared oral pharmaceutical preparations were subjected to a feline stomatitis treatment test. The results show that the dissolution rate data of the oral agents of the compounds shown in the formulas (I-1) to (I-6) prepared by the method in the example 7 are similar, and the dissolution rate of the prepared oral agent meets the requirements of the medicine; the prepared oral preparations of the compounds of the formulas (I-1) to (I-6) have good curative effect on the stomatitis of cats; the compounds of the formulas (I-1) to (I-6) have good curative effect on the feline stomatitis, and the curative effect of the injection of the compounds of the formulas (I-3), (I-4), (I-5) and (I-6) is slightly better than that of the injection of the compounds of the formulas (I-1) and (I-2).
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (9)
1. Nucleoside compoundThe application of the nucleoside compound in preparing the medicine for treating feline stomatitis caused by feline calicivirus is characterized in that the nucleoside compound has the following structure:
2. the use according to claim 1, wherein the medicament is prepared mainly from pharmaceutically acceptable adjuvants and the nucleoside compound as an active ingredient.
3. The use according to claim 2, wherein the medicament is an injection, and the content of the nucleoside compound in the injection is (5-20) mg/mL.
4. The use according to claim 3, wherein the adjuvant comprises a solvent selected from at least one of water, polyethylene glycol having an average molecular weight of 200-600, propylene glycol, ethanol, and isotonic sodium chloride solution.
5. The use of claim 4, wherein the solvent comprises ethanol, polyethylene glycol and propylene glycol, and the volume ratio of the ethanol, the polyethylene glycol and the propylene glycol is (1.5-2.5): (4.5-5.5): (2.5-4).
6. The use according to claim 4, wherein the injection comprises 1000mg of the nucleoside compound, 20 to 25mL of ethanol, 45 to 50mL of polyethylene glycol having an average molecular weight of 200 to 600, and 20 to 30mL of propylene glycol, in 100mL of the unit.
7. The use according to any one of claims 3 to 6, wherein the effective dose of the nucleoside compound in the injection is 0.1 to 10mg/kg body weight per day.
8. The use of claim 2, wherein the medicament is an oral formulation and the excipients include fillers, binders, disintegrants and lubricants;
the oral preparation comprises, by weight, 1-50 parts of the nucleoside compound, 5-95 parts of a filler, 1-10 parts of a binder, 1-20 parts of a disintegrant and 0-5 parts of a lubricant.
9. The use according to claim 8, wherein the medicament comprises 5 to 20 parts by weight of the nucleoside compound, 60 to 80 parts by weight of a filler, 3 to 10 parts by weight of a binder, 2 to 8 parts by weight of a disintegrant and 1 to 3 parts by weight of a lubricant.
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| CN112939981B (en) * | 2021-01-19 | 2022-08-26 | 嘉兴金派特生物科技有限公司 | Nucleoside compound, pharmaceutically acceptable salt, composition and application thereof |
| CN117298120A (en) * | 2022-06-28 | 2023-12-29 | 苏州旺山旺水生物医药股份有限公司 | A method for treating cat coronal or calicivirus infection |
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