Atropine pharmaceutical composition

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to an atropine pharmaceutical composition which contains pharmaceutically acceptable salt of atropine, sulfonic cation exchange resin and a suspending aid, and the suspending aid is selected from one or more of carbomer, povidone and hydroxyethyl cellulose. According to the atropine pharmaceutical composition formula, the content of free atropine in liquid medicine can be obviously reduced, so that the content of related substances can be controlled within a lower range, and the medicine has better stability under the room temperature condition and has a better medicine release effect.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to an atropine pharmaceutical composition. Background Art

[0002] Ion exchange resins have long been widely used in chemical production, hydrometallurgy, atomic energy industry, food industry, pharmaceutical industry, analytical chemistry and environmental protection. With the cross-disciplinary development, ion exchange resins are increasingly used as drug carriers in pharmacy, and there are already several marketed products, such as dextromethorphan hydrobromide controlled release suspension (Delsym), dihydrocodeine controlled release suspension (Histions) and betaxolol hydrochloride eye drops (Betex).

[0003] Ion exchange resins are classified according to their active groups, mainly into cation exchange resins containing acidic groups and anion exchange resins containing basic groups. Commonly used cation exchange resins include styrene resins and acrylic resins. The styrene resin skeleton is a polystyrene polymer, the active group is a sulfonic acid group, and the exchangeable cations are sodium ions or hydrogen ions. When used, the exchangeable cations (A + ) and the free cations in the solution (B + ) to exchange B + Fixed in the resin to form a complex. By using cation exchange resin technology, the purpose of masking the bad taste of drugs, promoting dissolution or increasing bioavailability can be achieved.

[0004] Some chemical drugs are unstable during production and storage due to their own properties. For example, atropine molecules contain small molecule ester bonds, conjugated double bonds and toluene-type side chain structures, and their structural stability is poor. During the preparation, production and long-term storage process, hydrolysis, oxidation, dehydration, rearrangement and other reactions are prone to occur, producing corresponding alcohols or acids or other intermediates. Conventional methods to improve stability include adjusting the pH value of the drug solution, lowering the storage temperature, etc., but the effect is not ideal or there are problems such as inconvenience in use, poor patient compliance, and high cost.

[0005] Regarding the stability of atropine molecules, Falan Li et al. proposed a new strategy in “Enhanced ophthalmic bioavailability and stability of atropine sulfate via sustained release particles using polystyrene sulfonate resin” to synthesize ophthalmic polystyrene sulfonate resin (SPSR) with spherical and uniform size for cation exchange with atropine sulfate (ATS). Xanthan gum and hydroxypropyl methylcellulose (HPMC) were added to the formula of ATS@SPSR suspension eye drops as suspending agents. In vitro studies showed that ATS@SPSR suspension eye drops had sustained release properties, and its degradation product, hydrochlorothiocarbazone, remained undetected for up to 30 days at 40°C. The ATS levels in the tears and aqueous humor of New Zealand rabbits showed that compared with conventional ATS eye drops, ATS@SPSR suspension eye drops had higher mean residence time (MRT) and area under the drug concentration-time curve (AUC 0-12 h ). In addition, the safety assessment confirmed that the ATS@SPSR suspension eye drops were non-irritating to rabbit eyes. However, there is still room for further improvement in the stability and drug release effect of the eye drops. And this method relies on spherical and uniformly sized (3-5μm) SPSRs to achieve the drug loading capacity of ATS and the efficacy of ATS@SPSR suspension eye drops, but SPSRs that meet the size requirements will bring additional costs in actual production and preparation, which will be detrimental to improving the market competitiveness of the drug. At the same time, the wavelength for measuring the purity of atropine in this article is 225nm, while the more suitable wavelength for measuring the purity of atropine is 210nm, so this method has poor separation between atropine and impurities, and the impurity results look better, but it is difficult to reflect the true purity of atropine. Summary of the invention

[0006] The object of the present invention is to provide an atropine pharmaceutical composition, which contains atropine pharmaceutically acceptable salt, sulfonic acid cation exchange resin and a suspending agent, wherein the suspending agent is selected from one or more of carbomer, povidone and hydroxyethyl cellulose.

[0007] As a preferred embodiment, the pharmaceutically acceptable salt of atropine is selected from one or more of atropine sulfate, atropine hydrobromide, atropine hydrochloride, and atropine phosphate.

[0008] As a preferred embodiment, the sulfonic acid cation exchange resin is selected from one or both of sodium poly(styrene divinyl benzene) sulfonate (PSS) and poly(styrene divinyl benzene) sulfonic acid (PSA).

[0009] As a preferred embodiment, the atropine pharmaceutical composition further contains an osmotic pressure regulator, and the osmotic pressure regulator is selected from one or more of glycerol, mannitol, sorbitol, and polyethylene glycol 400.

[0010] As a preferred embodiment, the content of the pharmaceutically acceptable salt of atropine is 0.005-1% (w / v), more preferably 0.008-0.05% (w / v).

[0011] As a preferred embodiment, the mass ratio of the sulfonic acid cation exchange resin to the pharmaceutically acceptable salt of atropine is greater than or equal to 1, more preferably greater than or equal to 5.

[0012] As a preferred embodiment, the content of the suspending agent is 0.01-10% (w / v); preferably, the suspending agent is 0.1-2% (w / v) hydroxyethyl cellulose, 0.05-1% (w / v) carbomer or 1-10% (w / v) povidone.

[0013] As a preferred embodiment, the atropine pharmaceutical composition further contains water, and the pH value of the atropine pharmaceutical composition is 5.0-6.5.

[0014] As a preferred embodiment, the atropine pharmaceutical composition further contains a pH regulator, and the pH regulator is selected from one or more of hydrochloric acid, sodium hydroxide, and carbomer.

[0015] As a preferred embodiment, the content of free atropine in total atropine is not higher than 30wt%, more preferably not higher than 21wt%, further preferably not higher than 15wt%, and further preferably not higher than 10wt%.

[0016] As a preferred embodiment, the content of total impurities and tropic acid impurities (i.e., impurity C) in the atropine pharmaceutical composition after storage at below 60° C. for 0 to 30 days is less than 7wt%, more preferably less than 6wt%, further preferably less than 4wt%, and further preferably less than 3wt%.

[0017] In some preferred embodiments, the content of anhydrous atropine impurity (i.e., impurity A) in the atropine pharmaceutical composition after storage at below 60° C. for 0 to 30 days is less than 0.10 wt %, more preferably less than 0.06 wt %, and further preferably 0 (i.e., not detected).

[0018] As a preferred embodiment, the osmotic pressure of the atropine pharmaceutical composition is 260-320 mOsmol / kg.

[0019] The atropine pharmaceutical composition formula of the present invention can significantly reduce the free atropine content in the drug solution, thereby controlling the content of related substances within a relatively low range, so that the drug has better stability at room temperature and has a better drug release effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0021] Figure 1 This is the in vitro release curve result in the example of the present invention. DETAILED DESCRIPTION

[0022] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention. Those skilled in the art may make various modifications and changes to the present invention without departing from the scope or spirit of the present invention. For example, a feature described or illustrated as part of one embodiment may be used in another embodiment to produce a further embodiment.

[0023] Unless otherwise indicated, the meaning of all terms (including technical and scientific terms) used to disclose the present invention is the same as that commonly understood by those of ordinary skill in the art to which the present invention belongs. By way of further guidance, the following definitions are used to better understand the teachings of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0024] The terms "and / or", "or / and", and "and / or" used in this article include any one of two or more related listed items, and also include any and all combinations of related listed items, and the arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions that are all connected by "logical and", and undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the combination of four of A, B, C, and D (that is, the technical solution that is all connected by "logical AND").

[0025] As used herein, the terms "comprising", "including" and "comprising" are synonymous and are inclusive or open-ended and do not exclude additional, unrecited members, elements or method steps.

[0026] Numerical ranges expressed as endpoints herein include all numbers and fractions subsumed within the range, as well as the recited endpoints.

[0027] The present invention relates to concentration values, and its meaning includes fluctuations within a certain range. For example, it can fluctuate within the corresponding accuracy range. For example, 2% can allow fluctuations within the range of ±0.1%. For values ​​that are large or do not require too fine control, its meaning is also allowed to include greater fluctuations. For example, 100mM can allow fluctuations within the range of ±1%, ±2%, ±5%, etc. Involving molecular weight, its meaning is allowed to include fluctuations of ±10%.

[0028] In the present invention, descriptions such as "plurality" and "multiple" refer to quantities greater than or equal to 2 unless otherwise specified.

[0029] In the present invention, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0030] In the present invention, “preferred”, “better”, “more preferred” and “suitable” are only used to describe implementation methods or examples with better effects. It should be understood that they do not constitute limitations on the scope of protection of the present invention.

[0031] In the present invention, "optionally", "optional", "optionally", "optionally", "optional", "optional", "optional" means optional, that is, it means to be selected from any one of the two parallel schemes of "yes" or "no". If multiple "optional" or "optional" appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "optional" or "optional" is independent.

[0032] In the present invention, the term "pharmaceutically acceptable salts of atropine" refers to some atropine salt forms used in pharmaceutical preparations, which are pharmaceutically considered to be safe, effective and suitable for preparations. Atropine is a widely used drug, mainly used to treat various diseases, such as cardiac abnormalities, ophthalmic diseases and certain poisoning conditions. In the present invention, the pharmaceutically acceptable salts of atropine particularly include salts of atropine acceptable in ophthalmic drugs.

[0033] In the present invention, the term "sulfonic acid cation exchange resin" refers to a resin whose active group is a sulfonic acid group (-SO3H) and can exchange with cations (positively charged ions). This type of resin is a polymer material, usually polymerized from monomers such as styrene and divinylbenzene to form a porous network structure. The sulfonic acid groups in the resin exchange with cations in the solution through an ion exchange reaction, thereby removing ions in the solution.

[0034] In the present invention, "% (w / v)" refers to "weight / volume percentage", which is a unit used to express the concentration of a solute in a solution, and represents the number of grams of the solute contained in every 100 ml of the solution.

[0035] In the present invention, "wt%" refers to the mass percentage.

[0036] The invention relates to an atropine pharmaceutical composition, which contains atropine pharmaceutically acceptable salt, sulfonic acid cation exchange resin and a suspending agent, wherein the suspending agent is selected from one or more of carbomer, polyvinylpyrrolidone (PVP for short) and hydroxyethylcellulose (HEC for short).

[0037] The present invention firstly finds that by loading atropine pharmaceutically acceptable salts on sulfonic acid cation exchange resins and providing the above-mentioned suspending agent, the free atropine content in the solution can be significantly reduced, and the degradation reaction of atropine can be slowed down as a whole, so as to achieve the effect of improving the stability of the preparation. At the same time, the above-mentioned atropine pharmaceutical composition also has high comfort and bioavailability.

[0038] In some embodiments, the pharmaceutically acceptable salt of atropine is selected from one or more of atropine sulfate, atropine hydrobromide, atropine hydrochloride, and atropine phosphate.

[0039] In some preferred embodiments, the pharmaceutically acceptable salt of atropine is atropine sulfate.

[0040] In some embodiments, the sulfonic acid cation exchange resin is selected from one or both of poly(styrene divinyl benzene) sodium sulfonate (PSS) and poly(styrene divinyl benzene) sulfonic acid (PSA). Both PSA and PSS have polystyrene macromolecule skeletons, the active groups are sulfonic acid groups, and the exchangeable cations are hydrogen ions and sodium ions, respectively.

[0041] In some embodiments, the atropine pharmaceutical composition further contains an osmotic pressure regulator, and the osmotic pressure regulator is a non-ionic agent.

[0042] In some preferred embodiments, the osmotic pressure regulator is selected from one or more of glycerol, mannitol, sorbitol, and polyethylene glycol 400. The use of the above osmotic pressure regulator can further reduce the content of free atropine in the drug solution.

[0043] In some further preferred embodiments, the osmotic pressure regulator is selected from one or both of glycerol and mannitol.

[0044] In some embodiments, the content of the pharmaceutically acceptable salt of atropine is 0.005-1% (w / v), more preferably 0.008-0.05% (w / v).

[0045] As an example, in some specific embodiments, the content of the pharmaceutically acceptable salt of atropine can be 0.005% (w / v), 0.008% (w / v), 0.01% (w / v), 0.012% (w / v), 0.015% (w / v), 0.02% (w / v), 0.05% (w / v), 0.1% (w / v), 0.5% (w / v), 1% (w / v) or any value between 0.005 and 1% (w / v).

[0046] In some embodiments, the mass ratio of the sulfonic acid cation exchange resin to the pharmaceutically acceptable salt of atropine is greater than or equal to 1, more preferably greater than or equal to 5. The greater the amount of the sulfonic acid cation exchange resin used, the stronger the ability to adsorb atropine salt, and the lower the content of free atropine in the solution. When the mass ratio of the sulfonic acid cation exchange resin to the pharmaceutically acceptable salt of atropine is greater than or equal to 1, the content of free atropine in the solution can be well controlled. When the mass ratio of the sulfonic acid cation exchange resin to the pharmaceutically acceptable salt of atropine is greater than or equal to 5, the amount of the sulfonic acid cation exchange resin is continued to be increased, the content of free atropine remains basically unchanged, and the load capacity reaches equilibrium. For PSS and PSA, due to different pH, the loading amount of atropine is slightly different, but as the dosage increases, the loading amount remains consistent in the final equilibrium state.

[0047] As an example, in some specific embodiments, the mass ratio of the pharmaceutically acceptable salt of atropine to the sulfonic acid cation exchange resin can be 1:1, 1:2, 1:3, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:7, 1:8 or a value greater than 1:8.

[0048] In the present invention, the particle size of the sulfonic acid cation exchange resin is not particularly limited. According to the research of the present invention, the particle size of the sulfonic acid cation exchange resin has no obvious effect on the adsorption amount of atropine salt. Therefore, in the specific implementation, those skilled in the art only need to consider the effect of particle size on the comfort and irritation of medication in combination with common sense. For example, referring to the requirements of the ophthalmic preparations of the 2020 edition of the Chinese Pharmacopoeia, the particle size should be controlled as follows: according to the particle size and particle size distribution determination method (General Rule 0982 First Method), the number of particles larger than 50μm in each smear shall not exceed 2 (except for those containing raw powder of decoction pieces), and particles larger than 90μm shall not be detected.

[0049] In some specific embodiments, the D90 of the sulfonic acid cation exchange resin is ≤40 μm, and the D50 is ≤20 μm. Sulfonic acid cation exchange resins meeting the above particle size requirements have better application effects in the present invention.

[0050] In some embodiments, the content of the suspending agent is 0.01-10% (w / v).

[0051] In some preferred embodiments, the suspending agent is hydroxyethyl cellulose having a content of 0.1 to 2% (w / v). As an example, the content of the hydroxyethyl cellulose can be 0.1% (w / v), 0.2% (w / v), 0.3% (w / v), 0.4% (w / v), 0.5% (w / v), 0.6% (w / v), 0.7% (w / v), 1.0% (w / v), 1.2% (w / v), 1.4% (w / v), 1.6% (w / v), 1.8% (w / v), 2.0% (w / v) or any value between 0.1 and 2.0% (w / v).

[0052] In some preferred embodiments, the suspending agent is a carbomer having a content of 0.05 to 1% (w / v). As an example, the content of the carbomer can be 0.05% (w / v), 0.08% (w / v), 0.1% (w / v), 0.12% (w / v), 0.15% (w / v), 0.17% (w / v), 0.2% (w / v), 0.4% (w / v), 0.6% (w / v), 0.8% (w / v), 1.0% (w / v) or any value between 0.05 and 1% (w / v). In some embodiments, when the atropine pharmaceutical composition does not contain cations, the content of carbomer can be reduced to 0.05 to 0.2% (w / v). In some embodiments, when cations are introduced into the atropine pharmaceutical composition, the viscosity will drop sharply, and the amount of carbomer can be appropriately adjusted within the above range.

[0053] In some preferred embodiments, the suspending agent is a polyvidone with a content of 1 to 10% (w / v). As an example, the content of the polyvidone can be 1.0% (w / v), 1.5% (w / v), 2.0% (w / v), 2.5% (w / v), 3.0% (w / v), 3.5% (w / v), 3.8% (w / v), 4.0% (w / v), 4.2% (w / v), 4.5% (w / v), 4.7% (w / v), 5.0% (w / v), 6.0% (w / v), 7.0% (w / v), 8.0% (w / v), 9.0% (w / v), 10.0% (w / v) or any value between 1 and 10% (w / v). The present invention does not particularly limit the type of povidone. In specific implementation, the povidone can be selected from any one or more of povidone K15, povidone K30, povidone K60, and povidone K90.

[0054] The specific dosage of the osmotic pressure regulator is not particularly limited in the present invention. Those skilled in the art can adjust the dosage of the osmotic pressure regulator to make the atropine pharmaceutical composition isotonic with tears (260-320 mOsmol / kg) in combination with the conditions of different osmotic pressure regulators. In some specific embodiments, the dosage of the osmotic pressure regulator is 2.0-6.0% (w / v).

[0055] In some specific embodiments, the osmotic pressure regulator is mannitol with a content of 4.0-6.0% (w / v). As an example, the dosage of the mannitol can be 4.0% (w / v), 4.5% (w / v), 5.0% (w / v), 5.5% (w / v), 6.0% (w / v) or any value between 4.0 and 6.0% (w / v). The dosage instructions here are only for the purpose of adjusting the atropine pharmaceutical composition to be isotonic with tears (260-320mOsmol / kg). Those skilled in the art can also adjust the dosage of mannitol to other values.

[0056] In some specific embodiments, the osmotic pressure regulator is glycerol with a content of 2.0-3.0% (w / v). As an example, the amount of glycerol can be 2.0% (w / v), 2.3% (w / v), 2.5% (w / v), 2.6% (w / v), 2.8% (w / v), 3.0% (w / v) or any value between 2.0 and 3.0% (w / v). The dosage instructions here are only for the purpose of adjusting the atropine pharmaceutical composition to be isotonic with tears (260-320mOsmol / kg). Those skilled in the art can also adjust the amount of glycerol to other values.

[0057] In some embodiments, the atropine pharmaceutical composition further contains water, and the pH value of the atropine pharmaceutical composition is 5.0 to 6.5. In the atropine pharmaceutical composition of the present invention, the cation exchange resin performs better in a low pH environment, so theoretically, it has a good technical effect when the pH value is below 6.5. Taking into account the comfort of eye medication, the pH value of the atropine pharmaceutical composition is limited to 5.0 to 6.5 in the present invention.

[0058] In some embodiments, the water can be water for injection (WFI) or purified water.

[0059] As an example, the pH value of the atropine pharmaceutical composition can be 5.0, 5.3, 5.5, 5.8, 6.0, 6.2, 6.5 or any value within the range of 5.0 to 6.5.

[0060] In some embodiments, the atropine pharmaceutical composition further comprises a pH regulator, wherein the pH regulator is selected from one or more of hydrochloric acid, sodium hydroxide, and carbomer. The pH regulator has no significant effect on the content of free atropine in the drug solution.

[0061] In some embodiments, the content of free atropine in the atropine pharmaceutical composition is not higher than 30wt%, more preferably not higher than 21wt%, further preferably not higher than 15wt%, further preferably not higher than 13wt%, further preferably not higher than 11wt%, further preferably not higher than 10wt%, further preferably not higher than 9wt%. The present invention also finds that when the free atropine content is within the above range, it will further help to reduce the generation rate of related substances in the drug solution, thereby helping to improve drug stability. And the lower the content of free atropine, the more conducive to improving drug stability.

[0062] In some embodiments, the atropine pharmaceutical composition is stored at below 60°C (such as room temperature, 40°C, 60°C, etc.) for 0 to 30 days (such as 0 days, 5 days, 10 days, 15 days, 20 days, 30 days, etc.), and the content of total impurities and tropic acid impurities (i.e., impurity C) is less than 7wt%, more preferably less than 6wt%, further preferably less than 4wt%, and further preferably less than 3wt%.

[0063] In some embodiments, the content of dehydrated atropine impurity (i.e., impurity A) in the atropine pharmaceutical composition after storage at below 60°C (e.g., room temperature, 40°C, 60°C, etc.) for 0 to 30 days (e.g., 0 days, 5 days, 10 days, 15 days, 20 days, 30 days, etc.) is less than 0.10wt%, more preferably less than 0.06wt%, and further preferably 0 (i.e., not detected).

[0064] In some embodiments, the osmotic pressure of the atropine pharmaceutical composition is 260-320 mOsmol / kg. As an example, the osmotic pressure of the atropine pharmaceutical composition can be 260 mOsmol / kg, 270 Osmol / kg, 280 Osmol / kg, 290 Osmol / kg, 300 Osmol / kg, 310 Osmol / kg, 320 mOsmol / kg, or any value between 260 and 320 mOsmol / kg.

[0065] In some preferred embodiments, the atropine pharmaceutical composition contains 0.005-0.015% (w / v) atropine sulfate, 0.4-0.6% (w / v) sodium poly(styrene divinyl benzene) sulfonate or poly(styrene divinyl benzene) sulfonic acid, 0.4-0.6% (w / v) hydroxyethyl cellulose, 4.0-6.0% (w / v) mannitol, and water, and the pH value is adjusted to 5.0-6.5 by hydrochloric acid and / or sodium hydroxide.

[0066] Those skilled in the art can also combine the above-mentioned embodiments with common sense to obtain more embodiments of the atropine pharmaceutical composition of the present invention.

[0067] The present invention further provides a method for preparing the atropine pharmaceutical composition, which comprises: mixing the components contained in the atropine pharmaceutical composition.

[0068] In some embodiments, when the pH value after mixing is not within the range of 5.0 to 6.5, the pH adjuster is used to adjust the pH value to 5.0 to 6.5.

[0069] In the present invention, the preparation method of the atropine pharmaceutical composition is not particularly limited. In specific implementation, those skilled in the art can combine common sense to mix the components in the atropine pharmaceutical composition to obtain the atropine pharmaceutical composition. During the mixing process, ultrasonic treatment or mechanical stirring can be used to enhance the dispersion uniformity of the drug.

[0070] As an example, in some specific embodiments, the preparation method of the atropine pharmaceutical composition includes: first stirring and adsorbing a pharmaceutically acceptable salt of atropine and a sulfonic acid cation exchange resin, and then centrifuging (optionally washing with pure water) to remove unadsorbed free atropine, and then mixing with other components in the atropine pharmaceutical composition to obtain the atropine pharmaceutical composition.

[0071] The present invention further provides a method for treating ophthalmic diseases, comprising: administering the atropine pharmaceutical composition to the patient's eyes.

[0072] Embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are preferably referred to the guidance provided in the present invention, and can also be based on the experimental manual or normal conditions in this area, and can also be based on other experimental methods known in the art, or according to the conditions recommended by the manufacturer.

[0073] In the following specific embodiments, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument test accuracy or operation accuracy are allowed.

[0074] Example 1: Cationic resin type and dosage screening

[0075] Atropine sulfate (API) and PSS / PSA are stirred and adsorbed in a weight ratio, the adsorbed preparation is centrifuged, and the active ingredient content in the supernatant is determined. The active ingredient content in the supernatant is the free atropine content that is not adsorbed by PSS / PSA.

[0076] Free atropine content detection method: the sample is centrifuged at 15000rpm for 30min, and the supernatant is diluted and injected. Octadecylsilane bonded silica gel is used as a filler (4.6mm×150mm, 5μm), and 0.05mol / L potassium dihydrogen phosphate solution (containing 0.0025mol / L sodium heptane sulfonate, and the pH value is adjusted to 5.0 with phosphoric acid or sodium hydroxide solution)-acetonitrile (84:16) is used as the mobile phase; the flow rate is 1.0ml per minute; the column temperature is 25℃; the detection wavelength is 225nm; the injection volume is 50μl. In the following examples, when the free atropine content is mentioned, it is detected using the detection method here.

[0077] The results are shown in Table 1 below, which shows that the greater the amount of PSS / PSA used, the stronger the ability to adsorb atropine, and the lower the free content in the solution. When the ratio reaches 1:5, the amount of PSS / PSA continues to increase, the free content remains basically unchanged, and the load capacity reaches equilibrium. The free content of atropine of different concentrations is basically consistent with the law of the amount of PSS / PSA used. PSS and PSA have slightly different loads of atropine due to different pH values, but as the amount increases, the load remains consistent in the final equilibrium state. Combined with the conclusion of Example 6 below, the lower the free atropine content, the more conducive to stability. Therefore, it is more preferred that the mass ratio of PSS / PSA to atropine sulfate is greater than or equal to 5 in the present invention.

[0078] Table 1

[0079]

[0080] The same amount of PSA and PSS were used as cationic resins to prepare samples to determine the free content of the drug solution. There was no significant difference in the results, as shown in Table 2. Therefore, both PSA and PSS can be used as cationic resins, and the dosage can be adjusted according to the target free content.

[0081] Table 2

[0082]

[0083] Example 2 Effect of PSS Particle Size

[0084] The exchange process of exchangeable cations in cation exchange resins and free cations in solution may be affected by the surface area of ​​the resin. Taking the free atropine content as the evaluation index of the adsorption effect, atropine sulfate: PSS = 1:2, PSS of different particle sizes were investigated, and the results are shown in Table 3 below. The results show that the particle size of PSS has no obvious effect on the adsorption amount of atropine. In ophthalmic preparations, the particle size of the inclusions is too large, and there are problems of medication comfort and irritation. Referring to the requirements of the ophthalmic preparations of the 2020 edition of the Chinese Pharmacopoeia, the particle size should be controlled as follows: according to the particle size and particle size distribution determination method (General Rule 0982 First Method), each smear shall not have more than 2 particles larger than 50μm (except for the original powder of the decoction piece), and particles larger than 90μm shall not be detected. In order to facilitate the comparison effect, in all the prescriptions in the embodiments, PSS uses PSS of uniform particle size from the same batch, and its D50 is less than 10 microns; PSA uses PSA of uniform particle size from the same batch, and its D50 is less than 10 microns.

[0085] Table 3

[0086]

[0087] Example 3 Effect of the type and amount of suspending agent

[0088] The addition of suspending agents can increase the viscosity of the dispersion medium and better maintain the dispersion state of the suspension. This example uses free atropine content, sedimentation volume ratio and redispersibility as indicators to explore the influence of the type and amount of suspending agents in the composition. Each prescription component and amount are shown in Table 4 below.

[0089] Table 4

[0090]

[0091] The viscosity was measured by rotational viscometer, and the sedimentation volume ratio was measured according to the method of the 2020 edition of the Chinese Pharmacopoeia. Redispersibility determination method: After the sample was placed for 24 hours, the product was shaken vigorously for 10 seconds, and the suspension was transferred to a test tube. The suspension and the inner wall of the container were checked, and there should be no visible lumps. The test results are shown in Table 5 below.

[0092] Taking the main degradation product impurity A (dehydrated atropine), impurity C (tropic acid) and total impurities as evaluation indicators, the stability test of prescription 1, prescription 15 and prescription 16 was carried out at high temperature 40℃ and 60℃, and the prescriptions with different free atropine contents were investigated. Related substance detection method: The sample was stirred with 1M potassium chloride solution (1:5 ratio) for 2h, centrifuged at 10000rpm for 10min, and the supernatant was sampled for detection. The chromatographic conditions were the same as the free atropine content detection method. The results are shown in Table 6 below.

[0093] According to the measurement results, sodium carboxymethyl cellulose and sodium hyaluronate can lead to an increase in the free atropine content, affecting the stability of the liquid medicine. Xanthan gum is a refined polysaccharide polymer, and one of the five sugar residues in the repeating unit contains a carboxylate and a corresponding cation, which leads to an increase in the free atropine content. The growth of related substances in the stability process is faster than that of the prescription using a non-ionic suspending agent, and it is not suitable to use a large amount in the prescription. Use with a non-ionic suspending agent can reduce this effect and improve stability, but the effect is still worse than the prescription of the present invention. Using hydroxyethyl cellulose, povidone K30, and carbomer has no obvious effect on the free atropine content, and the viscosity is different under different dosages, but the sedimentation volume ratio and redispersibility meet the requirements. Therefore, carbomer, povidone K30, and hydroxyethyl cellulose are selected as suspending agents, and the dosage should meet the requirements of sedimentation volume ratio and redispersibility.

[0094] Table 5

[0095]

[0096] Table 6

[0097]

[0098]

[0099] Note: ND means not detected.

[0100] Example 4 Effect of pH Regulator Type

[0101] The pH adjustment of the liquid medicine may affect the stability of the liquid medicine due to the change of the free atropine content caused by the introduction of ions. This example study compares the effects of carbomer, hydrochloric acid and sodium hydroxide as pH adjusters on the free atropine content. The prescription and results are shown in Table 7 below. The results show that the use of hydrochloric acid / sodium hydroxide to adjust the pH value only introduces a very small amount of cations, which has no significant effect on the free atropine content. Therefore, the type and amount of pH adjuster can be selected according to actual needs.

[0102] Table 7

[0103]

[0104] Example 5 Effect of the Type and Dosage of Osmotic Pressure Regulator

[0105] The ophthalmic preparation is used to adjust the osmotic pressure to be close to that of tears. This example uses the free atropine content as an indicator to compare the effects of the types of osmotic pressure regulators in the composition. The specific prescription is shown in Table 8 below.

[0106] Table 8

[0107]

[0108]

[0109] The results of the study showed that the free atropine content of the drug solution was significantly higher when the ionic osmotic pressure regulator sodium chloride was used to adjust the osmotic pressure than the non-ionic osmotic pressure regulators glycerol and mannitol. Therefore, the osmotic pressure regulator should be non-ionic, and the dosage should be adjusted to be isotonic with tears (260-320mOsmol / kg).

[0110] Example 6 Comparison of Stability of Compositions with Different Free Atropine Contents

[0111] Atropine has poor molecular structure stability and is easily degraded during production and storage. High temperature can aggravate the degradation of atropine. Using the main degradation product impurity A (anhydroatropine), impurity C (tropic acid) and total impurities as evaluation indicators, stability tests were conducted at high temperatures of 40°C and 60°C to investigate prescriptions with different free atropine contents.

[0112] Related substance detection methods:

[0113] Dilution: mobile phase A-acetonitrile = 75:25.

[0114] Test solution: Take about 2.0g of the product, weigh accurately, place in a 25ml volumetric flask, add about 20ml of diluent, oscillate at 200 rpm for at least 20min, dilute to scale with diluent, shake well, centrifuge at 14000 rpm for 15 minutes, and take the supernatant. (0.04mg / ml)

[0115] Reference solution: Take about 4 mg of atropine sulfate reference, place it in a 100 ml volumetric flask, add diluent to dissolve and dilute to the mark, shake well; take 1.0 ml, place it in a 100 ml volumetric flask, dilute to the mark with diluent, shake well. (0.4 μg / ml).

[0116] Sensitivity solution: Measure 1.0 ml of the reference solution, place it in a 10 ml volumetric flask, dilute to the mark with diluent, and shake well. (0.04 μg / ml)

[0117] System suitability solution: Weigh appropriate amounts of atropine sulfate reference substance, impurity C reference substance, 2-phenylacrylic acid reference substance and impurity A reference substance respectively, dissolve them in diluent and quantitatively dilute them to make a mixed solution containing approximately 10 μg each of atropine sulfate, impurity C, 2-phenylacrylic acid and impurity A per 1 ml.

[0118] Chromatographic conditions: octadecylsilane bonded silica gel is used as filler (2.1mm×100mm, 3.5μm or equivalent); concentrated ammonia solution-water (1:100) (pH adjusted to 3.0 with perchloric acid) is used as mobile phase A, acetonitrile is used as mobile phase B, and gradient elution is performed according to Table 9 below; flow rate is 0.4ml per minute; column temperature is 30℃; detection wavelength is 210nm; injection volume is 15μl.

[0119] Table 9

[0120]

[0121] The results are shown in Table 10 below: The free atropine content has a significant effect on related substances. The lower the free atropine content, the slower the growth of the main degradation product impurity C and the better the stability. Under high temperature conditions of 60°C-30 days, when the free atropine content is 30%, the impurity C is 5.73%, and the total impurities are 5.92%; when the free atropine content is 56%, the impurity C is 9.96%, and the total impurities are 10.42%. According to the current version of the USP quality standard for atropine sulfate eye drops, impurity C shall not exceed 7.0%, and total impurities shall not exceed 7.0%. Therefore, the ratio of free atropine content to total atropine content in the solution should not be higher than 30%.

[0122] Table 10

[0123]

[0124]

[0125] Note: ND means not detected.

[0126] Example 7 Comparison of the stability of different concentrations of formula and ordinary atropine solution

[0127] The concentration of atropine sulfate in the formula is low. Except for the sodium poly(styrene divinyl benzene) sulfonate that forms the complex, formulas of different concentrations can be prepared using the same type and amount of excipients. According to the ratio of atropine sulfate: sodium poly(styrene divinyl benzene) sulfonate = 1:5 (w:w), 0.05% and 0.01% solutions (Formulation 17 and Formula 14) were prepared respectively, and stability studies were conducted together with ordinary atropine solutions (Formulation 13) with the same pH value prepared using sodium chloride as an osmotic pressure regulator. The specific formulas of each formula are shown in Table 11, and the results are shown in Table 12 below. At the same time, the osmotic pressure, viscosity, sedimentation volume ratio, and redispersibility of Formula 14 and Formula 17 were also tested, and the results are shown in Table 11.

[0128] The test results show that there is no significant difference in the test results of osmotic pressure, viscosity, sedimentation volume ratio, redispersibility and other indicators between prescription 14 and prescription 17, indicating that the same type and amount of excipients can be used in formulations of different concentrations except sodium poly(styrene divinylbenzene) sulfonate. The results of high temperature stability at 40°C show that the growth trend of impurity C and total impurities in prescriptions 17 and 14 is significantly lower than that of prescription 13, and the stability is good. According to this growth trend, the stability meets the requirement of long-term storage of samples at room temperature not exceeding 25°C.

[0129] It is known in the art that the lower the concentration of atropine sulfate, the worse the stability. Therefore, although prescription 13 contains 0.05% atropine sulfate, and some prescriptions of the present invention contain 0.01% atropine sulfate, the prescription of the present invention is still better than prescription 13 containing 0.05% atropine sulfate even when it contains 0.01% atropine sulfate. The effect comparison is sufficient to illustrate the significant advantage of the atropine pharmaceutical composition of the present invention in terms of stability compared with ordinary atropine solution.

[0130] Table 11

[0131]

[0132] Table 12

[0133]

[0134] Note: ND means not detected.

[0135] Example 8 In vitro release experiment

[0136] The in vitro release of prescription 17 using PSS technology and prescription 13 of ordinary atropine solution was tested by dynamic dialysis. Prepare fresh simulated tear fluid (STF), divide it into 250mL beakers, seal it with plastic wrap and place it in a constant temperature oscillator at 37℃±1℃ for preheating. Cut off 8cm of the treated dialysis bag, take 4mL of the preparation to be tested into the dialysis bag, seal it with a sealing clip to ensure that the preparation to be tested will not leak, put the dialysis bag containing the preparation to be tested into the preheated dispersion medium, oscillate at a speed of 50rpm, take 3mL of the preparation at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8h and add an equal amount of fresh STF solution.

[0137] Results Figure 1 ,The results showed that the prescription 17 using PSS technology was slowly released within 8 h, which could effectively prolong the release time of atropine sulfate and reduce the initial release amount.

[0138] Example 9 Pharmacokinetics of the preparation in tears and aqueous humor

[0139] The pharmacokinetic test method of tears is as follows: The pharmacokinetics of the prescription using PSS technology (prescription 1) and the ordinary atropine solution prescription (0.01% specification, the only difference from prescription 13 is that it contains 0.01% atropine sulfate) in the tears of New Zealand rabbits were studied. Prescription 1 or ordinary atropine solution prescription (0.01% specification) was instilled into the conjunctiva of the left eye of 6 New Zealand rabbits, and the eyelids were gently closed for 30 seconds. Tear samples were collected at 0.083, 0.25, 0.5, 1, 1.5, 2, 3, 4, 8 and 12 hours after administration for analysis to determine the atropine concentration.

[0140] The pharmacokinetic test method of aqueous humor is as follows: 6 rabbits were randomly divided into two groups and given prescription 1 eye drops (n=3) and ordinary atropine solution prescription (0.01% specification) eye drops (n=3), respectively. The atropine content of aqueous humor test samples was collected at 0.17, 0.5, 1, 2, 3, 4, 8 and 12 hours after administration.

[0141] The results are shown in Table 13.

[0142] Table 13

[0143]

[0144] The results of the pharmacokinetic test of tears showed that the AUC of the PSS technology prescription 0-t and C max The concentrations of T are 6.4 and 2.2 times those of ordinary atropine solution, respectively. 1 / 2 It was also significantly extended from 1.86h of ordinary solution to 8.11h, indicating that the use of PSS technology can prolong the retention time of atropine on the ocular surface and improve its bioavailability.

[0145] The results of aqueous humor pharmacokinetic tests showed that the AUC 0-t From 21.04±5.76ng·h / ml to 126.44±27.22ng·h / ml, C max From 9.25±3.92ng / ml to 48.19±13.73ng / ml, T 1 / 2 It is 5 times that of ordinary atropine solution, C max Increased 4 times.

[0146] In addition, in the atropine pharmaceutical composition of the present invention, compared with the prescription containing 0.01% atropine sulfate, when the content of atropine sulfate is 0.05% (such as the above-mentioned prescription 17), the pharmacokinetic detection effect is better.

[0147] The above-mentioned embodiments only express several implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. An atropine pharmaceutical composition comprising atropine pharmaceutically acceptable salt, a sulfonic acid cation exchange resin and a suspending agent, in, The suspending agent is selected from one or more of carbomer, povidone and hydroxyethyl cellulose.

2. The atropine pharmaceutical composition according to claim 1, wherein The pharmaceutically acceptable salt of atropine is selected from one or more of atropine sulfate, atropine hydrobromide, atropine hydrochloride, and atropine phosphate.

3. The atropine pharmaceutical composition according to claim 1 or 2, wherein The sulfonic acid cation exchange resin is selected from one or both of sodium poly(styrene divinyl benzene) sulfonate and poly(styrene divinyl benzene) sulfonic acid.

4. The atropine pharmaceutical composition according to any one of claims 1 to 3, wherein The atropine pharmaceutical composition further contains an osmotic pressure regulator, and the osmotic pressure regulator is selected from one or more of glycerol, mannitol, sorbitol, and polyethylene glycol 400.

5. The atropine pharmaceutical composition according to any one of claims 1 to 4, wherein The content of the pharmaceutically acceptable salt of atropine is 0.005-1% (w / v), more preferably 0.008-0.05% (w / v).

6. The atropine pharmaceutical composition according to any one of claims 1 to 5, wherein The mass ratio of the sulfonic acid cation exchange resin to the pharmaceutically acceptable salt of atropine is greater than or equal to 1, and more preferably greater than or equal to 5.

7. The atropine pharmaceutical composition according to any one of claims 1 to 6, wherein The content of the suspending agent is 0.01-10% (w / v); preferably, the suspending agent is 0.1-2% (w / v) hydroxyethyl cellulose, 0.05-1% (w / v) carbomer or 1-10% (w / v) povidone.

8. The atropine pharmaceutical composition according to any one of claims 1 to 7, wherein The atropine pharmaceutical composition further contains water, and the pH value of the atropine pharmaceutical composition is 5.0-6.

5.

9. The atropine pharmaceutical composition according to any one of claims 1 to 8, wherein The atropine pharmaceutical composition further contains a pH regulator, and the pH regulator is selected from one or more of hydrochloric acid, sodium hydroxide, and carbomer.

10. The atropine pharmaceutical composition according to any one of claims 1 to 9, wherein The content of free atropine in total atropine is no more than 30wt%, more preferably no more than 21wt%, and further preferably no more than 10wt%.

11. The atropine pharmaceutical composition according to any one of claims 1 to 10, wherein The contents of total impurities and tropic acid impurities in the atropine pharmaceutical composition after storage at below 60° C. for 0 to 30 days are all lower than 7wt%, more preferably lower than 6wt%, further preferably lower than 4wt%, and further preferably lower than 3wt%.

12. The atropine pharmaceutical composition according to any one of claims 1 to 11, wherein The osmotic pressure of the atropine pharmaceutical composition is 260-320 mOsmol / kg.

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