WO2023036227A1 - Gouttes ophtalmiques d'atropine et leur procédé de préparation - Google Patents

Gouttes ophtalmiques d'atropine et leur procédé de préparation Download PDF

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Publication number
WO2023036227A1
WO2023036227A1 PCT/CN2022/117758 CN2022117758W WO2023036227A1 WO 2023036227 A1 WO2023036227 A1 WO 2023036227A1 CN 2022117758 W CN2022117758 W CN 2022117758W WO 2023036227 A1 WO2023036227 A1 WO 2023036227A1
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Prior art keywords
atropine
eye drops
regulator
osmotic pressure
present
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PCT/CN2022/117758
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English (en)
Chinese (zh)
Inventor
袁建栋
李�昊
冯欣
黄仰青
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浙江视方极医药科技有限公司
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Priority to CN202280020882.0A priority Critical patent/CN117295491A/zh
Priority to KR1020247010782A priority patent/KR20240052048A/ko
Publication of WO2023036227A1 publication Critical patent/WO2023036227A1/fr

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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
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • 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
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia

Definitions

  • the invention belongs to the field of medicine, and in particular relates to an atropine eye drop and a preparation method thereof.
  • Atropine is a natural compound that can be extracted from belladonna or other plants of the nightshade family.
  • atropine is mainly used to relieve smooth muscle spasm, improve microcirculation, inhibit glandular secretion, and relieve the inhibition of vagus nerve on the heart.
  • Atropine sulfate (atropine sulfate) is a kind of salt of atropine, according to clinical data records, the pharmacological action of atropine sulfate ophthalmic preparation is better, has quite high selectivity to M receptor, and blocks M choline receptor, makes The pupillary sphincter and ciliary muscles relax, creating a pupil dilating mechanism that relieves pain caused by eye swelling and inflammation.
  • Atropine ophthalmic preparations can stretch the originally tense ciliary muscles of adolescents and children, and further restore their regulatory function during sleep, effectively delaying and treating the development of myopia.
  • atropine ophthalmic preparations such as Meioupin, Yatromin, Letropine, USP1%, etc.
  • related substances such as Meioupin, Yatromin, Letropine, USP1%, etc.
  • the present invention provides an atropine eye drop, which has good stability and low total impurities through selection of raw materials and optimization of prescription.
  • the present invention also provides a method for preparing the above-mentioned atropine eye drops.
  • the atropine eye drops prepared by this method have good stability and low total impurities, and are suitable for long-term storage.
  • the invention provides an atropine eye drop, which comprises the following components: in terms of mass concentration, 0.10-0.20 g/L of atropine or a pharmaceutically acceptable salt thereof, 0-1.00 g/L of a chelating agent, and 7.80 g/L of an osmotic pressure regulator ⁇ 9.00g/L, pH regulator and water for injection;
  • the pH regulator is a combination of citric acid and borax or a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid, and the dosage of the pH regulator is based on adjusting the pH value to 4.5-5.5.
  • citric acid is 0.50-2.00 g/L
  • borax is 1.00-2.00 g/L
  • the pharmaceutically acceptable salt is sulfate.
  • the chelating agent is disodium edetate.
  • the present invention provides a kind of preparation method of atropine eye drops according to the present invention, comprises the following steps:
  • the temperature of the water for injection is below 40°C.
  • the solution B is filtered through a microfiltration membrane with a pore size of 0.22 ⁇ m, and the microfiltration membrane is a PVDF membrane.
  • numerical range represented by "numerical value A - numerical value B" means the range which includes numerical value A and B of an end point.
  • the pH regulator is a combination of citric acid and borax or a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid, and the dosage of the pH regulator is based on adjusting the pH value to 4.5-5.5.
  • citric acid in terms of mass concentration, in the combination of the above-mentioned citric acid and borax, citric acid is 0.50 ⁇ 2.00g/L, and borax is 1.00 ⁇ 2.00g/L; in terms of mass concentration, the above-mentioned phosphoric acid
  • sodium dihydrogen phosphate in the combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid, sodium dihydrogen phosphate is 1.49-6.00 g/L, disodium hydrogen phosphate is 0.43-0.88 g/L, and hydrochloric acid is 0.04-0.13 g/L.
  • the atropine eye drop provided by the invention has good stability, low total impurities and is suitable for long-term storage through selection of raw materials and optimization of prescription; moreover, the pH value is 4.5-5.5, which is closer to neutral, and has no irritation to eyes.
  • the atropine eye drops consist of the following components: in terms of mass concentration, 0.10-0.20 g/L of atropine or a pharmaceutically acceptable salt thereof, and 0-1.00 g/L of a chelating agent , osmotic pressure regulator 7.80 ⁇ 9.00g/L, pH regulator and water for injection;
  • the pH regulator is a combination of citric acid and borax or a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid; in terms of mass concentration, 0.50-2.00 g/L of citric acid and 1.00-2.00 g/L of borax , sodium dihydrogen phosphate 1.49 ⁇ 6.00g/L, disodium hydrogen phosphate 0.43 ⁇ 0.88g/L, hydrochloric acid 0.04 ⁇ 0.13g/L.
  • the present invention further optimizes above-mentioned prescription, makes it not contain thickening agent (for example hypromellose (60SH)), can avoid the influence of thickening agent on product stability; Ammonium, etc.), high safety and low toxicity.
  • thickening agent for example hypromellose (60SH)
  • Atropine or a pharmaceutically acceptable salt thereof in terms of mass concentration, atropine or a pharmaceutically acceptable salt thereof is 0.10 to 0.20 g/L, for example, its mass concentration can be 0.10 g/L, 0.12 g/L, 0.14g/L, 0.15g/L, 0.16g/L, 0.18g/L, 0.20g/L, etc.
  • the mass concentration of atropine or a pharmaceutically acceptable salt thereof is 0.10 g/L or 0.20 g/L.
  • the pharmaceutically acceptable salt is sulfate (ie, atropine sulfate).
  • the packaging container used for atropine eye drops may be made of low-density polyethylene, and its raw materials contain metal elements harmful to the human body; moreover, in actual production, the liquid distribution tank and production pipelines are made of stainless steel. It is also possible to introduce metal ions. Trace heavy metals can catalyze the decomposition of active ingredients in atropine eye drops through oxidation or other mechanisms. Therefore, the addition of chelating agents can form stable complexes with various metal ions to prevent the decomposition of active ingredients and make atropine drops The eye fluid has good stability and low total impurities.
  • the chelating agent includes one or a combination of two or more of edetate disodium, edetate sodium calcium and edetate.
  • the osmotic pressure regulator includes one or a combination of two or more of sodium chloride, mannitol and glycerin.
  • the osmotic pressure regulator is sodium chloride, and the stability of the atropine eye drops using sodium chloride is better than that using mannitol or glycerin.
  • the osmotic pressure range that the human eye can tolerate is relatively wide, which is equivalent to the osmotic pressure molar concentration of 0.5-1.5% w/v sodium chloride solution.
  • eye drops should be isotonic with tear fluid, equivalent to 0.09% w/v sodium chloride solution.
  • the dosage of osmotic pressure regulator should be comprehensively examined.
  • the mass concentration of the osmotic pressure regulator is 7.80-9.00 g/L.
  • its mass concentration can be 7.80 g/L, 8.00 g/L, 8.20 g/L, 8.40 g/L, 8.60g/L, 8.80g/L, 9.00g/L, etc.
  • mass concentration is lower than 7.80g/L or higher than 9.00g/L, the osmotic pressure will exceed the tolerance range of human eyes, thus causing eye discomfort.
  • the mass concentration of the osmotic pressure regulator is 8.30 g/L and 8.70 g/L.
  • the pH regulator is used to adjust the pH value of the atropine eye drops to 4.5-5.5, making it close to neutral and non-irritating to the eyes.
  • the molecular structure of atropine or atropine sulfate contains an ester group, which is prone to hydrolysis when the pH value is high, and its hydrolyzed products are tropic acid and tropine alcohol, thus causing quality problems of eye drops.
  • the pH regulator is a combination of citric acid and borax.
  • the pH regulator is a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid.
  • the atropine eye drops include the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable salt is 0.10 to 0.20 g/L, chelating agent 0 ⁇ 1.00g/L, osmotic pressure regulator 7.80 ⁇ 9.00g/L, citric acid 0.50 ⁇ 2.00g/L, borax 1.00 ⁇ 2.00g/L and water for injection.
  • the atropine eye drop comprises the following components: in terms of mass concentration, 0.10-0.20 g/L of atropine or a pharmaceutically acceptable salt thereof, 0-1.00 g/L of a chelating agent, and Osmotic pressure regulator 7.80 ⁇ 9.00g/L, citric acid 0.50g/L, borax 1.05g/L and water for injection.
  • the atropine eye drops include the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable Accepted salt 0.10-0.20g/L, chelating agent 0-1.00g/L, osmotic pressure regulator 7.80-9.00g/L, sodium dihydrogen phosphate 1.49-6.00g/L, disodium hydrogen phosphate 0.43-0.88g/L L, hydrochloric acid 0.04 ⁇ 0.13g/L and water for injection.
  • the atropine eye drop comprises the following components: in terms of mass concentration, atropine or its pharmaceutically acceptable salt 0.10 ⁇ 0.20g/L, chelating agent 0 ⁇ 1.00g/L, osmotic pressure Regulator 7.80 ⁇ 9.00g/L, sodium dihydrogen phosphate 1.95g/L, disodium hydrogen phosphate 0.56g/L, hydrochloric acid 0.076g/L and water for injection.
  • the dosage specification of atropine eye drops is 0.5mL/bottle, which is suitable for single administration by the user, and there is no problem of drug contamination, which is safer and more reliable.
  • the invention provides the preparation method of above-mentioned atropine eye drops, comprises the following steps:
  • the atropine eye drops prepared by this method have good stability, low total impurities and are suitable for long-term storage.
  • solution B is filtered through a microfiltration membrane with a pore size of 0.22 ⁇ m.
  • Atropine eye drops is a sterile preparation, and the purpose of filtering through a microfiltration membrane is to sterilize and make the product meet the standard.
  • at least two microfiltration membranes are provided, and the sterilization effect is better.
  • the pH regulator when the pH regulator is a combination of citric acid and borax, the "combination of citric acid and borax" represents the solute existence form of the pH regulator in the atropine eye drops.
  • the added The raw material can be a mixture of anhydrous citric acid or its hydrate and borax or its hydrate, specifically, it can be a mixture of anhydrous citric acid and borax, or it can be a mixture of citric acid monohydrate and borax decahydrate. For mixtures, etc., the amount added is based on the mass concentration of the solute.
  • the preparation method of atropine eye drops comprises the following steps:
  • the pH regulator is a combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid
  • the combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid means the pH regulator in atropine eye drops.
  • the raw material added can be the mixture of sodium dihydrogen phosphate or its hydrate, disodium hydrogen phosphate or its hydrate and hydrochloric acid, such as sodium dihydrogen phosphate dihydrate, dihydrogen phosphate A mixture of sodium dihydrate and hydrochloric acid, etc.; wherein the hydrochloric acid can be commercially available concentrated hydrochloric acid, or dilute hydrochloric acid of other concentrations prepared by oneself.
  • the preparation method of atropine eye drops comprises the following steps:
  • the present embodiment provides the preparation method of above-mentioned atropine eye drops, comprises the following steps:
  • the present embodiment provides a kind of atropine eye drops, and its prescription is as shown in table 2:
  • the present embodiment provides the preparation method of above-mentioned atropine eye drops, comprises the following steps:
  • the present embodiment provides a kind of atropine eye drops, and its prescription is as shown in table 3:
  • the present embodiment provides the preparation method of above-mentioned atropine eye drops, comprises the following steps:
  • Adjust the pH value to 5.00 with 0.1mol/L hydrochloric acid add water for injection to 1000mL to obtain solution A, and measure the pH value of the system to 5.00;
  • the present embodiment provides a kind of atropine eye drops, and its prescription is as shown in table 4:
  • the present embodiment provides the preparation method of above-mentioned atropine eye drops, comprises the following steps:
  • Adjust the pH value to 5.00 with 0.1mol/L hydrochloric acid add water for injection to 1000mL to obtain solution A, and measure the pH value of the system to 5.01;
  • Adopted pH regulator among the embodiment 1 and embodiment 2 is the combination of citric acid and borax.
  • the test of its influencing factors investigated the conditions of high temperature (40°C and 50°C) and strong light irradiation (5000lx); considering the possible transportation conditions, low temperature test (4°C) and freezing Melt test (-18 °C) investigation.
  • the inspection results are shown in Table 5 and Table 6 respectively:
  • Anhydroatropine an impurity in related substances, is obtained by dehydration of atropine, which has an antispasmodic effect and is highly toxic.
  • the content of atropine sulfate in the atropine eye drops provided by the present invention is on the rise at high temperatures of 40°C and 50°C, and the content of atropine sulfate at 50°C is higher than that at 40°C.
  • the inner packaging material used in the atropine eye drops provided by the present invention is a semi-permeable container, which has the property of dehydration, which leads to an increase in the content of atropine sulfate in the eye drops.
  • the atropine eye drops provided by the invention under the conditions of high temperature of 50° C. and strong light irradiation, the growth trend of tropic acid and dehydrated atropine is remarkable. Therefore, the atropine eye drops provided by the invention should avoid high temperature and strong light irradiation during storage and transportation.
  • the pH adjuster that embodiment 3 and embodiment 4 adopt is the combination of sodium dihydrogen phosphate, disodium hydrogen phosphate and hydrochloric acid.
  • its influencing factor test investigated the conditions of high temperature (40°C and 50°C) and strong light irradiation (5000lx); considering the possible transportation conditions, low temperature test (4°C) and freezing Melt test (-18 °C) investigation. The investigation results are shown in Table 7 and Table 8 respectively:
  • the content of atropine sulfate in the atropine eye drops provided by the present invention shows an upward trend at high temperatures of 40°C and 50°C, and the content of atropine sulfate at 50°C is higher than that at 40°C.
  • the inner packaging material used in the atropine eye drops provided by the present invention is a semi-permeable container, which has the property of dehydration, which leads to an increase in the content of atropine sulfate in the eye drops.
  • the atropine eye drops provided by the invention under the conditions of high temperature of 50° C. and strong light irradiation, the growth trend of tropic acid and dehydrated atropine is remarkable. Therefore, the atropine eye drops provided by the invention should avoid high temperature and strong light irradiation during storage and transportation.
  • the self-made sample 1 is consistent with the prescription of Example 1, and the batch size is 100mL;
  • the self-made sample 2 is the atropine eye drops prepared in Example 1;
  • the self-made sample 3 is the same as the prescription of Example 3, and the batch size is 100mL;
  • Sample 4 is the atropine eye drops prepared in Example 3;
  • self-made sample 5 is consistent with the prescription of Example 3, and the batch size is 500mL.
  • self-made sample 1 is the atropine eye drops prepared in Example 1;
  • self-made sample 2 is the atropine eye drops prepared in Example 3;
  • self-made sample 3 has the same prescription as Example 3, and the batch size is 500mL.
  • the self-made eye drops of the present invention produce less unknown impurities, and the unknown impurities are caused by the complexity of the sample retention environment in the light stabilization box used, and its total impurities are still low.
  • the self-made eye drops of the present invention should be kept away from light.
  • self-made sample 1 is consistent with the prescription in Example 1, and the batch size is 100 mL; self-made sample 2 is consistent with the prescription in Example 3, and the batch size is 100 mL.
  • the tropic acid of the self-made eye drops is slightly higher than that of the commercially available eye drops—the American and European products during the accelerated 3-month period.
  • the reason is that the pH value of the American and European products is 4.7.
  • the pH value of eye drops is closer to 5.0, and tropic acid is greatly affected by the pH value, so the tropic acid of self-made eye drops will be slightly higher.
  • Tropic acid is a hydrolysis product of atropine, and it is a metabolite in the body.
  • the limit of tropic acid is 7.0%, so the tropic acid of self-made eye drops will not impact on security.
  • the content of tropic acid was significantly increased in commercially available eye drops.
  • the content of tropic acid, anhydroatropine and the largest unknown single impurity in the self-made eye drops remained at a low level, and the impurities produced were less, and the total impurities were lower than those in the commercial eye drops, and the stability was more stable. good.
  • the preparation method of the above prescription can be prepared according to the preparation method of Example 1-2. Specifically, the corresponding product was prepared according to the preparation method of Example 1.
  • the atropine eye drop provided by the invention does not contain thickening agent, has good stability and low total impurities, and is suitable for long-term storage.
  • the phosphate concentration was halved to examine its effect on sample stability. See Table 14 to Table 15 for the sample prescription composition and experimental results.
  • the mass concentrations of sodium dihydrogen phosphate and disodium hydrogen phosphate are preliminarily determined as 1.95g/L and 0.56g/L respectively, and the influence of sodium chloride dosage on osmotic pressure is investigated under these conditions. Blank excipient solutions containing different NaCl concentrations were prepared and the osmolarity of the samples was determined. The sample formulation and osmotic pressure results are shown in Table 16.
  • the present invention selects an osmotic pressure range of 280-320 mOsmol/kg, and the corresponding sodium chloride dosage is 7.80-9.00 g/L.
  • the osmotic pressure of the atropine eye drops of the present invention is preliminarily determined as about 300mOsmol/kg, and the corresponding sodium chloride consumption is 8.30g/L this moment, expand the sodium chloride concentration to A study of stability effects.
  • Samples were prepared according to the prescription after adjusting the amount of sodium chloride, and the stability of the samples was investigated. See Table 17 to Table 18 for the sample prescription composition and experimental results.
  • the amount of sodium chloride is adjusted from 9.00g/L to 8.30g/L, which does not affect the stability of the sample. This shows that under the condition of ensuring product stability, the concentration of sodium chloride should be further reduced The amount used can improve the safety and overall quality of atropine eye drops.
  • the mass concentrations of sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium chloride are 1.49 ⁇ 6.00g/L, 0.43 ⁇ 0.88g/L and 7.80 ⁇ 9.00g/L respectively. g/L; and, the present invention is further screened, and when the mass concentrations of sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium chloride are respectively 1.95g/L, 0.56g/L, and 8.30g/L, the eye drops The stability is better.

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Abstract

La présente invention se rapporte au domaine de la médecine, et concerne spécifiquement des gouttes ophtalmiques d'atropine et leur procédé de préparation. Les gouttes ophtalmiques d'atropine selon la présente invention comprennent : en masse, de 0,10 à 0,20 g/L d'atropine ou d'un sel pharmaceutiquement acceptable de celle-ci, de 0 à 1,00 g/L d'un agent chélatant, et de 7,80 à 9,00 g/L d'un régulateur de pression osmotique, un régulateur de pH et de l'eau pour injection. Le régulateur de pH est une combinaison d'acide citrique et de borax ou une combinaison de dihydrogénophosphate de sodium, du phosphate d'hydrogène disodique et de l'acide chlorhydrique, et la quantité du régulateur de pH utilisée est basée sur le réglage de la valeur de pH à 4,5-5,5. Les gouttes ophtalmiques d'atropine préparées selon la prescription ci-dessus ont une bonne stabilité, de faibles impuretés totales, une faible toxicité et n'irritent pas les yeux.
PCT/CN2022/117758 2021-09-13 2022-09-08 Gouttes ophtalmiques d'atropine et leur procédé de préparation WO2023036227A1 (fr)

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CN110934816A (zh) * 2018-09-25 2020-03-31 沈阳兴齐眼药股份有限公司 一种提高低浓度阿托品眼用制剂稳定性的方法
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