Atropine pharmaceutical composition

Abstract

The present invention belongs to the field of pharmaceutical formulations, and specifically relates to an atropine pharmaceutical composition, comprising an atropine pharmaceutically acceptable salt, a sulfonic acid-based cation exchange resin, and a suspending agent. The suspending agent is selected from one or more of carbomer, povidone, and hydroxyethyl cellulose. The formulation of the atropine pharmaceutical composition of the present invention can significantly reduce the content of free atropine in a medicinal solution and thus can control the content of related substances within a relatively low range, so that the drug has superior stability at room temperature and a superior drug release effect.

Description

An atropine drug composition

[0001] Cross-references to related applications

[0002] This invention claims priority to Chinese Patent Application No. 2024114482041, filed on October 16, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of pharmaceutical preparations, and specifically relates to an atropine pharmaceutical composition. Background Technology

[0004] Ion exchange resins have long been widely used in various fields such as chemical production, hydrometallurgy, nuclear energy industry, food industry, pharmaceutical industry, analytical chemistry, and environmental protection. With the development of interdisciplinary integration, ion exchange resins are increasingly used as drug carriers in pharmaceutics, and several marketed products have been developed, such as dextromethorphan hydrobromide controlled-release suspension (Delsym), dihydrocodeine controlled-release suspension (Histions), and betalol hydrochloride eye drops (Betshow).

[0005] 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-based resins and acrylic resins. Styrene-based resins have a polystyrene polymer backbone, with sulfonic acid groups as the active groups, and exchangeable cations such as sodium ions or hydrogen ions. During use, the exchangeable cations (A...) in the resin... + ) and free cations (B) in the solution + To exchange B, thus making B + It is immobilized in the resin to form a complex. By using cation exchange resin technology, it is possible to mask unpleasant drug tastes, promote solubility, or increase bioavailability.

[0006] Some chemical drugs are unstable during production and storage due to their inherent properties. For example, atropine contains small molecule ester bonds, conjugated double bonds, and toluene-type side chains, resulting in poor structural stability. During preparation, production, and long-term storage, it is prone to hydrolysis, oxidation, dehydration, rearrangement, and other reactions, producing corresponding alcohols, acids, or other intermediate products. Conventional methods to improve stability include adjusting the pH of the drug solution and lowering the storage temperature, but these methods are not very effective or have drawbacks such as inconvenience in use, poor patient compliance, and high costs.

[0007] Regarding the stability of atropine molecules, Falan Li et al. proposed a novel strategy in their paper "Enhanced ophthalmic bioavailability and stability of atropine sulfate via sustained release particles using polystyrene sulfonate resin" to perform cation exchange with atropine sulfate (ATS) by synthesizing ophthalmic polystyrene sulfonate resin (SPSR) with spherical and uniform size. Xanthan gum and hydroxypropyl methylcellulose (HPMC) were added as suspending agents to the formulation of ATS@SPSR suspension eye drops. In vitro studies showed that ATS@SPSR suspension eye drops have sustained release characteristics, and its degradation product—fluorochloric acid—remained undetectable for up to 30 days at 40°C. ATS levels in the tear film and aqueous humor of New Zealand rabbits indicated that, compared to conventional ATS eye drops, ATS@SPSR suspension eye drops showed significantly lower mean residence time (MRT) and area under the drug concentration-time curve (AUC). 0-12h The concentration of atropine increased significantly. Furthermore, safety assessments confirmed the non-irritating nature of the ATS@SPSR suspension eye drops on rabbit eyes. However, there is still room for improvement in the stability and drug release effect of this eye drop. This method relies on spherical and uniformly sized (3–5 μm) SPSRs to achieve the drug loading capacity of ATS and the efficacy of the ATS@SPSR suspension eye drops; however, SPSRs meeting this size requirement would incur additional costs in actual production, which would be detrimental to enhancing the drug's market competitiveness. Additionally, the wavelength used in this article to determine atropine purity was 225 nm, while the more suitable wavelength for determining atropine purity is 210 nm. Therefore, this method has poor separation between atropine and impurities, making the impurity results appear better and failing to reflect the true purity of atropine. Summary of the Invention

[0008] The purpose of this invention is to provide an atropine pharmaceutical composition comprising a pharmaceutically acceptable salt of atropine, a 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.

[0009] 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.

[0010] As a preferred embodiment, the sulfonic acid-based cation exchange resin is selected from one or both of sodium poly(styrene-divinylbenzene) sulfonate (PSS) and poly(styrene-divinylbenzene) sulfonic acid (PSA).

[0011] As a preferred embodiment, the atropine pharmaceutical composition further comprises an osmotic pressure regulator selected from one or more of glycerol, mannitol, sorbitol, and polyethylene glycol 400.

[0012] As a preferred embodiment, the content of pharmaceutically acceptable salts of the atropine is 0.005–1% (w / v), more preferably 0.008–0.05% (w / v).

[0013] 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.

[0014] 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.

[0015] As a preferred embodiment, the atropine pharmaceutical composition further contains water, and the pH value of the atropine pharmaceutical composition is 5.0 to 6.5.

[0016] As a preferred embodiment, the atropine pharmaceutical composition further comprises a pH adjuster selected from one or more of hydrochloric acid, sodium hydroxide, and carbomer.

[0017] As a preferred embodiment, the content of free atropine in the total atropine is not more than 30 wt%, more preferably not more than 21 wt%, further preferably not more than 15 wt%, and even more preferably not more than 10 wt%.

[0018] As a preferred embodiment, the total impurities and troponic acid impurities (i.e., impurity C) of the atropine drug composition after being stored at below 60°C for 0 to 30 days are all less than 7 wt%, more preferably less than 6 wt%, even more preferably less than 4 wt%, and even more preferably less than 3 wt%.

[0019] In some preferred embodiments, the content of dehydrated atropine impurities (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 even more preferably 0 (i.e., not detected).

[0020] As a preferred embodiment, the osmotic pressure of the atropine pharmaceutical composition is 260–320 mOsmol / kg.

[0021] The atropine pharmaceutical composition formulation of the present invention can significantly reduce the content of free atropine in the drug solution, thereby controlling the content of related substances within a low range, enabling the drug to have better stability at room temperature and better drug release effect. Attached Figure Description

[0022] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0023] Figure 1 shows the in vitro release curve results in an embodiment of the present invention. Detailed Implementation

[0024] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the invention. Those skilled in the art can make various modifications and variations to the invention without departing from its scope or spirit. For example, features described or illustrated as part of one embodiment can be used in another embodiment to produce further embodiments.

[0025] Unless otherwise stated, all terms used to disclose this invention (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Further guidance is provided below for a better understanding of the teachings of this invention. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0026] The terms "and / or," "or / and," and "and / or" as used herein include any one of two or more of the related listed items, as well as any and all combinations of the related listed items. These 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 connected by "logical AND," and also undoubtedly includes technical solutions connected by "logical OR." For example, "A and / or B" includes three parallel solutions: 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, a technical solution that is connected by "logical OR"), as well as any and all combinations of A, B, C, and D, that is, combinations of any two or three of A, B, C, and D, and also combinations of all four of A, B, C, and D (that is, a technical solution that is connected by "logical AND").

[0027] The terms “containing,” “comprising,” and “including” as used in this invention are synonyms and are inclusive or open-ended, and do not exclude additional, uncited members, elements, or method steps.

[0028] In this invention, the numerical range represented by endpoints includes all numerical values ​​and fractions contained within that range, as well as the endpoints mentioned.

[0029] This invention relates to concentration values, which include fluctuations within a certain range. For example, fluctuations are allowed within a corresponding precision range. For instance, 2% may fluctuate within ±0.1%. For larger values ​​or values ​​that do not require overly precise control, even greater fluctuations are permitted. For example, 100mM may fluctuate within ranges of ±1%, ±2%, ±5%, etc. Regarding molecular weight, fluctuations of ±10% are allowed.

[0030] In this invention, the terms "multiple" or "various" are used unless otherwise specified, referring to a quantity of 2 or more.

[0031] In this invention, the technical features described in an open-ended manner include both closed-ended technical solutions composed of the listed features and open-ended technical solutions that include the listed features.

[0032] In this invention, terms such as "preferred," "better," "more suitable," and "ideal" are merely descriptions of more effective implementation methods or embodiments, and should be understood not to limit the scope of protection of this invention.

[0033] In this invention, "optionally," "optionally," "optionally," "optionally," "optionally," and "optional" mean that they are optional, that is, they are selected from either "with" or "without." If multiple "optional" or "optional" terms appear in a technical solution, unless otherwise specified and there are no contradictions or mutual constraints, then each "optional" or "optional" term is independent.

[0034] In this invention, the term "pharmaceutically acceptable salt of atropine" refers to certain forms of atropine salt used in pharmaceutical preparations that are pharmaceutically considered safe, effective, and suitable for use in formulations. Atropine is a widely used drug primarily for the treatment of various conditions, such as cardiac abnormalities, eye diseases, and certain poisonings. In this invention, the pharmaceutically acceptable salts of atropine particularly include salts of atropine acceptable in ophthalmic pharmaceuticals.

[0035] In this invention, the term "sulfonic acid-based cation exchange resin" refers to a resin whose active group is a sulfonic acid group (-SO3H), capable of undergoing an exchange reaction with cations (positively charged ions). These resins are polymer materials, typically polymerized from monomers such as styrene and divinylbenzene, forming 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 from the solution.

[0036] In this invention, "% (w / v)" refers to "weight / volume percentage", a unit used to express the concentration of solute in a solution. It represents the number of grams of solute contained in 100 milliliters of solution.

[0037] In this invention, "wt%" refers to the percentage content by mass.

[0038] This invention relates to an atropine pharmaceutical composition comprising a pharmaceutically acceptable salt of atropine, a sulfonic acid cation exchange resin, and a suspending agent, wherein the suspending agent is selected from one or more of carbomer, polyvinylpyrrolidone (PVP), and hydroxyethylcellulose (HEC).

[0039] This invention first discovers that by loading a pharmaceutically acceptable salt of atropine onto a sulfonic acid-based cation exchange resin and incorporating the aforementioned suspending agent, the content of free atropine in the solution can be significantly reduced, thereby slowing down the overall degradation reaction of atropine and improving the stability of the formulation. Simultaneously, the aforementioned atropine drug composition also exhibits high comfort and bioavailability.

[0040] 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.

[0041] In some preferred embodiments, the pharmaceutically acceptable salt of atropine is atropine sulfate.

[0042] In some embodiments, the sulfonic acid-based cation exchange resin is selected from one or both of sodium poly(styrene-divinylbenzene)sulfonate (PSS) and poly(styrene-divinylbenzene)sulfonic acid (PSA). Both PSA and PSS have a polystyrene polymer backbone, with sulfonic acid groups as the active groups, and exchangeable cations of hydrogen ions and sodium ions, respectively.

[0043] In some embodiments, the atropine pharmaceutical composition further comprises an osmotic pressure regulator, which is a nonionic reagent.

[0044] In some preferred embodiments, the osmotic pressure regulator is selected from one or more of glycerol, mannitol, sorbitol, and polyethylene glycol 400. Using the above-mentioned osmotic pressure regulator can further reduce the free atropine content in the drug solution.

[0045] In some further preferred embodiments, the osmotic pressure regulator is selected from one or both of glycerol and mannitol.

[0046] In some embodiments, the content of pharmaceutically acceptable salts of the atropine is 0.005 to 1% (w / v), more preferably 0.008 to 0.05% (w / v).

[0047] As an example, in some specific embodiments, the content of the pharmaceutically acceptable salt of atropine can be any value between 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 0.005 to 1% (w / v).

[0048] In some embodiments, the mass ratio of the sulfonic acid-based 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 sulfonic acid-based cation exchange resin used, the stronger its ability to adsorb atropine salt, and the lower the content of free atropine in the solution. When the mass ratio of the sulfonic acid-based 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-based cation exchange resin to the pharmaceutically acceptable salt of atropine is greater than or equal to 5, further increasing the amount of sulfonic acid-based cation exchange resin does not significantly change the content of free atropine, and the loading capacity reaches equilibrium. For PSS and PSA, the loading capacity for atropine differs slightly due to different pH values, but as the amount increases, the loading capacity remains consistent in the final equilibrium state.

[0049] 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.

[0050] In this invention, the particle size of the sulfonic acid-based cation exchange resin is not particularly limited. Research conducted in this invention has shown that the particle size of the sulfonic acid-based cation exchange resin has no significant effect on the adsorption capacity of atropine salt. Therefore, in practical implementation, those skilled in the art only need to consider the impact of particle size on medication comfort and irritation based on common sense. For example, referring to the requirements of the 2020 edition of the Chinese Pharmacopoeia for ophthalmic preparations, the particle size should be controlled as follows: determined by the particle size and particle size distribution determination method (General Rule 0982, Method 1), no more than two particles larger than 50 μm should be present in each smear (except for raw powder of medicinal slices), and no particles larger than 90 μm should be detected.

[0051] In some specific embodiments, the sulfonic acid-based cation exchange resin has a D90 ≤ 40 μm and a D50 ≤ 20 μm. Sulfonic acid-based cation exchange resins meeting the above particle size requirements exhibit superior application effects in this invention.

[0052] In some embodiments, the content of the suspending agent is 0.01 to 10% (w / v).

[0053] In some preferred embodiments, the suspending agent is hydroxyethyl cellulose at a content of 0.1% to 2% (w / v). As an example, the content of the hydroxyethyl cellulose can be any value between 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 0.1% to 2.0% (w / v).

[0054] In some preferred embodiments, the suspending agent is carbomer at a content of 0.05–1% (w / v). As an example, the carbomer content can be any value between 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 0.05–1% (w / v). In some embodiments, when the atropine pharmaceutical composition does not contain a cation, the carbomer content can be reduced to 0.05–0.2% (w / v). In some embodiments, when a cation is introduced into the atropine pharmaceutical composition, the viscosity decreases sharply, and the carbomer dosage can be appropriately increased within the above range.

[0055] In some preferred embodiments, the suspending agent is povidone at a content of 1-10% (w / v). As an example, the content of the povidone can be any value between 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 1-10% (w / v). In this invention, the type of povidone is not particularly limited. In specific implementation, the povidone can be selected from any one or more of povidone K15, povidone K30, povidone K60 and povidone K90.

[0056] The specific dosage of the osmotic pressure regulator is not particularly limited in this invention. Those skilled in the art can adjust the dosage of the osmotic pressure regulator to achieve isotonicity (260-320 mOsmol / kg) between the atropine drug composition and tears, taking into account different osmotic pressure regulators. In some specific embodiments, the dosage of the osmotic pressure regulator is 2.0-6.0% (w / v).

[0057] In some specific embodiments, the osmotic pressure regulator is mannitol at a content of 4.0–6.0% (w / v). As an example, the amount of mannitol used can be any value between 4.0% (w / v), 4.5% (w / v), 5.0% (w / v), 5.5% (w / v), 6.0% (w / v), or 4.0–6.0% (w / v). The dosage descriptions here are merely illustrative for the purpose of adjusting the atropine pharmaceutical composition to be isotonic with tears (260–320 mOsmol / kg), and those skilled in the art can adjust the mannitol dosage to other values.

[0058] In some specific embodiments, the osmotic pressure regulator is glycerol at a content of 2.0–3.0% (w / v). As an example, the amount of glycerol used can be any value between 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 2.0–3.0% (w / v). The dosage descriptions herein are merely illustrative examples for the purpose of adjusting the atropine pharmaceutical composition to be isotonic with tears (260–320 mOsmol / kg), and those skilled in the art can adjust the amount of glycerol to other values.

[0059] In some embodiments, the atropine pharmaceutical composition further contains water, and the pH value of the atropine pharmaceutical composition is 5.0–6.5. In the atropine pharmaceutical composition of the present invention, the cation exchange resin performs better in a low pH environment. Therefore, theoretically, a pH value below 6.5 has good technical effects. Taking into account the comfort of ocular medication, the pH value of the atropine pharmaceutical composition is limited to 5.0–6.5 in the present invention.

[0060] In some specific embodiments, the water may be water for injection (WFI) or purified water.

[0061] As an example, the pH value of the atropine pharmaceutical composition can be any value within the range of 5.0, 5.3, 5.5, 5.8, 6.0, 6.2, 6.5 or 5.0 to 6.5.

[0062] In some embodiments, the atropine pharmaceutical composition further comprises a pH adjuster selected from one or more of hydrochloric acid, sodium hydroxide, and carbomer. The aforementioned pH adjuster has no significant effect on the content of free atropine in the pharmaceutical solution.

[0063] In some embodiments, the content of free atropine in the atropine pharmaceutical composition is no more than 30 wt% of the total atropine, more preferably no more than 21 wt%, even more preferably no more than 15 wt%, even more preferably no more than 13 wt%, even more preferably no more than 11 wt%, even more preferably no more than 10 wt%, and even more preferably no more than 9 wt%. The present invention has also found that when the content of free atropine is within the above-mentioned range, it is more beneficial to reduce the formation rate of related substances in the drug solution, thereby improving drug stability. Furthermore, the lower the content of free atropine, the more beneficial it is to improving drug stability.

[0064] In some embodiments, the total impurities and troponic acid impurities (i.e., impurity C) of the atropine drug composition after being stored at temperatures 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.) are all less than 7 wt%, more preferably less than 6 wt%, even more preferably less than 4 wt%, and even more preferably less than 3 wt%.

[0065] In some embodiments, the content of dehydrated atropine impurities (i.e., impurity A) in the atropine pharmaceutical composition after being stored at temperatures 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 0.10 wt%, more preferably less than 0.06 wt%, and even more preferably 0 (i.e., not detected).

[0066] 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 any value between 260 mOsmol / kg, 270 mOsmol / kg, 280 mOsmol / kg, 290 mOsmol / kg, 300 mOsmol / kg, 310 mOsmol / kg, 320 mOsmol / kg, or 260–320 mOsmol / kg.

[0067] 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(divinylbenzene) sulfonate or poly(divinylbenzene) sulfonic acid, 0.4–0.6% (w / v) hydroxyethyl cellulose, 4.0–6.0% (w / v) mannitol, and water, and the pH is adjusted to 5.0–6.5 by hydrochloric acid and / or sodium hydroxide.

[0068] 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.

[0069] The present invention further provides a method for preparing the above-mentioned atropine pharmaceutical composition, which includes: mixing the components contained in the atropine pharmaceutical composition.

[0070] In some embodiments, when the pH value after mixing is not in the range of 5.0 to 6.5, the pH adjuster is used to adjust the pH value to 5.0 to 6.5.

[0071] In this invention, the preparation method of the atropine drug composition is not particularly limited. In practice, those skilled in the art can mix the components of the atropine drug composition using common knowledge to obtain the atropine drug composition. During the mixing process, ultrasonic treatment or mechanical stirring can be used to enhance the uniformity of drug dispersion.

[0072] As an example, in some specific embodiments, the preparation method of the atropine drug composition includes: first stirring and adsorbing a pharmaceutically acceptable salt of atropine and a sulfonic acid cation exchange resin, then removing unadsorbed free atropine by centrifugation (optionally washing with pure water), and then mixing it with other components in the atropine drug composition to obtain the atropine drug composition.

[0073] The present invention further provides a treatment method for an ophthalmic disease, comprising: administering the atropine pharmaceutical composition to the patient's eye.

[0074] The embodiments of the present invention will be described in detail below with reference to examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. For experimental methods in the following embodiments where specific conditions are not specified, please refer to the guidelines given in this invention, or follow experimental manuals or conventional conditions in the art, or other experimental methods known in the art, or follow the conditions recommended by the manufacturer.

[0075] In the specific embodiments described below, the measurement parameters involving raw material components may have slight deviations within the weighing accuracy range unless otherwise specified. Temperature and time parameters are subject to acceptable deviations due to instrument testing accuracy or operational precision.

[0076] Example 1: Screening of cationic resin types and dosages

[0077] Atropine sulfate (API) was stirred and adsorbed with PSS / PSA in a weight ratio. The adsorbed formulation was then centrifuged, and the content of the active ingredient in the supernatant was determined. The content of the active ingredient in the supernatant is the content of free atropine that was not adsorbed by PSS / PSA.

[0078] Method for detecting free atropine content: The sample was centrifuged at 15000 rpm for 30 min, and the supernatant was diluted before injection. Octadecylsilane-bonded silica gel (4.6 mm × 150 mm, 5 μm) was used as the stationary phase, with 0.05 mol / L potassium dihydrogen phosphate solution (containing 0.0025 mol / L heptanesulfonate, pH adjusted to 5.0 with phosphoric acid or sodium hydroxide solution) - acetonitrile (84:16) as the mobile phase; the flow rate was 1.0 mL / min; the column temperature was 25 °C; the detection wavelength was 225 nm; and the injection volume was 50 μL. In the following examples, when the free atropine content is mentioned, the detection method described herein is used.

[0079] The results are shown in Table 1 below. These results indicate that the higher the PSS / PSA dosage, the stronger the atropine adsorption capacity and the lower the free content in the solution. When the ratio reaches 1:5, further increasing the PSS / PSA dosage does not significantly change the free content, indicating that the loading capacity has reached equilibrium. The free content of atropine at different concentrations follows a consistent pattern with the amount of PSS / PSA used. Due to differences in pH, PSS and PSA exhibit slightly different atropine loading capacities, but these capacities remain consistent at the final equilibrium state as the dosage increases. Based on the conclusions of Example 6 below, a lower free atropine content is more beneficial to stability. Therefore, in this invention, a mass ratio of PSS / PSA to atropine sulfate greater than or equal to 5 is preferred.

[0080] Table 1

[0081] Samples were prepared using the same amounts of PSA and PSS as cation exchange resins, and the free drug content in the solution was determined. No significant difference was observed in the results (see Table 2 below). Therefore, both PSA and PSS can be used as cation exchange resins, and the dosage can be adjusted according to the target free drug content.

[0082] Table 2

[0083] Example 2: Effect of PSS Particle Size

[0084] The exchange process between exchangeable cations and free cations in solution within a cation exchange resin may be affected by the resin surface area. Using the free atropine content as an evaluation index for adsorption effect, with atropine sulfate:PSS = 1:2, different particle sizes of PSS were investigated, and the results are shown in Table 3 below. The results show that the particle size of PSS has no significant effect on the adsorption capacity of atropine. In ophthalmic preparations, excessively large particle sizes can lead to issues with medication comfort and irritation. Referring to the requirements of the 2020 edition of the Chinese Pharmacopoeia for ophthalmic preparations, the particle size should be controlled as follows: determined by the particle size and particle size distribution determination method (General Rule 0982, Method 1), no more than two particles larger than 50 μm should be present in each smear (except for raw powders), and no particles larger than 90 μm should be detected. To facilitate comparison of effects, in all formulations of the examples, PSS of the same batch with a uniform particle size and a D50 of less than 10 micrometers was used; PSA of the same batch with a uniform particle size and a D50 of less than 10 micrometers was also used.

[0085] Table 3

[0086] Example 3: Effect of type and dosage of suspending agent

[0087] The addition of suspending agents can increase the viscosity of the dispersion medium, thus better maintaining the dispersion state of the suspension. This example uses free atropine content, sedimentation volume ratio, and redispersibility as indicators to investigate the effects of the type and amount of suspending agents on the composition. The components and amounts of each formulation are shown in Table 4 below.

[0088] Table 4

[0089] Viscosity was determined using a rotational viscometer method, and sedimentation volume ratio was determined according to the method in the 2020 edition of the Chinese Pharmacopoeia. Redispersibility was determined by: after the sample had been stored for 24 hours, shaking the sample vigorously for 10 seconds, transferring the suspension to a test tube, and examining the suspension and the inner wall of the container; no visible lumps should be present. The results are shown in Table 5 below.

[0090] Using the main degradation products, impurity A (dehydrated atropine), impurity C (tropic acid), and total impurities as evaluation indicators, formulations 1, 15, and 16 were subjected to stability tests at high temperatures of 40℃ and 60℃ to investigate formulations with different free atropine contents. Related substances detection method: samples were treated with 1M potassium chloride solution (1:5 ratio) with stirring for 2 h, centrifuged at 10000 rpm for 10 min, and the supernatant was injected for detection. Chromatographic conditions were the same as the method for detecting free atropine content. The results are shown in Table 6 below.

[0091] The test results show that sodium carboxymethyl cellulose and sodium hyaluronate increase the content of free atropine, affecting the stability of the drug solution. Xanthan gum, a refined polysaccharide polymer, contains a carboxylate group and a corresponding cation in one of its five sugar residues in its repeating unit, leading to an increase in free atropine content. During the stabilization process, the growth of related substances is faster than in formulations using non-ionic suspending agents, making it unsuitable for large-scale use in such formulations. Combining it with non-ionic suspending agents can reduce this effect and improve stability, but the effect is still inferior to the formulation of this invention. The use of hydroxyethyl cellulose, povidone K30, and carbomer has no significant effect on the free atropine content; different dosages result in different viscosities, but the sedimentation volume ratio and redispersibility meet the requirements. Therefore, carbomer, povidone K30, and hydroxyethyl cellulose are selected as suspending agents, and their dosages should meet the requirements for sedimentation volume ratio and redispersibility.

[0092] Table 5

[0093] Table 6

[0094] Note: ND indicates not detected.

[0095] Example 4: Effect of pH Adjuster Type

[0096] Adjusting the pH of the drug solution can affect its stability by introducing ions, which can alter the free atropine content. This study compared the effects of carbomer, hydrochloric acid, and sodium hydroxide as pH adjusters on the free atropine content. The formulations and results are shown in Table 7 below. The results show that adjusting the pH with hydrochloric acid / sodium hydroxide introduces only a very small amount of cations and has no significant effect on the free atropine content. Therefore, the type and amount of pH adjuster can be selected according to actual needs.

[0097] Table 7

[0098] Example 5: Effect of type and dosage of osmotic pressure regulator

[0099] Ophthalmic formulations use agents that regulate osmotic pressure similar to those used in tears. This example compares the effects of different types of osmotic pressure regulators in the composition, using free atropine content as an indicator. Specific formulations are shown in Table 8 below.

[0100] Table 8

[0101] The results showed that when using the ionic osmotic pressure regulator sodium chloride to adjust osmotic pressure, the free atropine content in the drug solution was significantly higher than that of the non-ionic osmotic pressure regulators glycerol and mannitol. Therefore, non-ionic osmotic pressure regulators should be selected, and the dosage should be adjusted to be isotonic with tears (260–320 mOsmol / kg).

[0102] Example 6: Comparison of stability of compositions with different free atropine contents

[0103] Atropine has poor molecular structural stability and is easily degraded during production and storage; high temperatures can exacerbate this degradation. Using the main degradation products, impurity A (dehydrated atropine), impurity C (tropine acid), and total impurities as evaluation indicators, stability tests were conducted at high temperatures of 40℃ and 60℃ to investigate formulations with different free atropine contents.

[0104] Related substances detection methods:

[0105] Diluent: Mobile phase A - Acetonitrile = 75:25.

[0106] Test solution: Accurately weigh approximately 2.0 g of this product and place it in a 25 ml volumetric flask. Add approximately 20 ml of diluent and shake at 200 rpm for at least 20 minutes. Dilute to the mark with the diluent, mix well, and centrifuge at 14,000 rpm for 15 minutes. Collect the supernatant. (0.04 mg / ml)

[0107] Reference solution: Take about 4 mg of atropine sulfate reference standard, place it in a 100 ml volumetric flask, add diluent to dissolve and dilute to the mark, and shake well; measure 1.0 ml, place it in a 100 ml volumetric flask, dilute to the mark with diluent, and shake well. (0.4 μg / ml).

[0108] Sensitivity solution: Measure 1.0 ml of the reference solution into a 10 ml volumetric flask, dilute to the mark with diluent, and mix well. (0.04 μg / ml)

[0109] System suitability solution: Weigh appropriate amounts of atropine sulfate reference standard, impurity C reference standard, 2-phenylacrylic acid reference standard and impurity A reference standard, dissolve them in diluent and dilute quantitatively to prepare a mixed solution containing approximately 10 μg each of atropine sulfate, impurity C, 2-phenylacrylic acid and impurity A per ml.

[0110] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (2.1 mm × 100 mm, 3.5 μm or equivalent); mobile phase A was concentrated ammonia solution-water (1:100) (pH adjusted to 3.0 with perchloric acid), and mobile phase B was acetonitrile, with gradient elution according to Table 9; flow rate was 0.4 mL / min; column temperature was 30 °C; detection wavelength was 210 nm; injection volume was 15 μl.

[0111] Table 9

[0112] The results are shown in Table 10 below: The content of free atropine has a significant impact on related substances. The lower the content of free atropine, the slower the growth of the main degradation product, impurity C, and the better the stability. Under high temperature conditions of 60℃ for 30 days, when the free atropine content is 30%, impurity C is 5.73% and total impurities are 5.92%; when the free atropine content is 56%, impurity C is 9.96% and total impurities are 10.42%. According to the current USP quality standard for atropine sulfate eye drops, impurity C should not exceed 7.0%, and total impurities should not exceed 7.0%. Therefore, the ratio of free atropine content to total atropine content in the solution should not exceed 30%.

[0113] Table 10

[0114] Note: ND indicates not detected.

[0115] Example 7: Stability comparison of different concentration formulations and ordinary atropine solution

[0116] The formulations contain low concentrations of atropine sulfate. Except for sodium poly(divinylbenzene styrene)sulfonate, which forms a complex, different concentration formulations can be prepared using the same type and amount of excipients. 0.05% and 0.01% solutions (Formula 17 and Formula 14) were prepared using atropine sulfate:sodium poly(divinylbenzene styrene)sulfonate ratio of 1:5 (w:w), respectively. These solutions were then compared with a standard atropine solution (Formula 13) prepared using sodium chloride as an osmotic pressure regulator at the same pH value, and stability studies were conducted. The specific formulations for each product are shown in Table 11, and the results are shown in Table 12 below. Simultaneously, the osmotic pressure, viscosity, sedimentation volume ratio, and redispersibility of Formulas 14 and 17 were also tested, and the results are shown in Table 11.

[0117] The test results show that there are no significant differences in osmotic pressure, viscosity, sedimentation volume ratio, and redispersibility between formulations 14 and 17, indicating that the same type and amount of excipients, except for sodium poly(divinylbenzene)sulfonate, can be used in formulations of different concentrations. High-temperature stability at 40℃ shows that the growth trends of impurity C and total impurities in formulations 17 and 14 are significantly lower than those in formulation 13, indicating good stability. Based on this growth trend, the stability meets the requirements for long-term storage at room temperature not exceeding 25℃.

[0118] It is known in the art that the lower the concentration of atropine sulfate, the worse its stability. Therefore, although formulation 13 contains 0.05% atropine sulfate, while some formulations of the present invention contain 0.01% atropine sulfate, the formulations of the present invention are still superior to formulation 13 containing 0.05% atropine sulfate, even when containing 0.01% atropine sulfate. The comparison of their effects is sufficient to demonstrate the significant advantage of the atropine pharmaceutical composition of the present invention in terms of stability compared to ordinary atropine solutions.

[0119] Table 11

[0120] Table 12

[0121] Note: ND indicates not detected.

[0122] Example 8 In vitro release experiment

[0123] The in vitro release rates of formulation 17 using PSS technology and formulation 13 using ordinary atropine solution were tested using dynamic dialysis. Fresh simulated tear fluid (STF) was prepared, dispensed into 250 mL beakers, sealed with plastic wrap, and preheated in a constant temperature shaker at 37℃±1℃. An 8 cm section of the prepared dialysis bag was cut, and 4 mL of the test formulation was placed in the dialysis bag. The bag was sealed with a sealing clip to ensure no leakage of the test formulation. The dialysis bag containing the test formulation was placed in the preheated dispersion medium and shaken at 50 rpm. At time points of 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 h, 3 mL of the formulation was collected and an equal volume of fresh STF solution was added.

[0124] The results are shown in Figure 1. The results show that formulation 17, which uses PSS technology, releases slowly over 8 hours, which can effectively prolong the release time of atropine sulfate and reduce the initial release amount.

[0125] Example 9: Pharmacokinetics of the Formulation in Tears and Aqueous Humidity

[0126] The pharmacokinetic assay of tears was performed as follows: The pharmacokinetics of formulation 1 (using PSS technology) and a standard atropine solution (0.01% strength, differing from formulation 13 only in that it contains 0.01% atropine sulfate) in the tears of New Zealand rabbits were studied. Formulation 1 or a standard atropine solution (0.01% strength) was instilled into the conjunctiva of the left eye of six 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.

[0127] The pharmacokinetic assay of aqueous humor was performed as follows: Six rabbits were randomly divided into two groups, one group was given prescription 1 eye drops (n=3), and the other group was given ordinary atropine solution prescription (0.01% strength) eye drops (n=3). The atropine content in aqueous humor samples was collected at 0.17, 0.5, 1, 2, 3, 4, 8 and 12 h after administration.

[0128] The results are shown in Table 13.

[0129] Table 13

[0130] Pharmacokinetic analysis of tears showed that the AUC of the PSS-based formulation was [data missing]. 0-t and C max These are 6.4 times and 2.2 times that of ordinary atropine solution, respectively. T 1 / 2 The retention time of atropine in the ocular surface was significantly extended from 1.86 h in the ordinary solution to 8.11 h, indicating that the PSS technology can prolong the retention time of atropine on the ocular surface and improve its bioavailability.

[0131] Pharmacokinetic analysis of aqueous humor showed that, using PSS technology, formulation 1 had an AUC of 0-t The concentration increased from 21.04±5.76 ng·h / ml to 126.44±27.22 ng·h / ml, C max The concentration increased from 9.25±3.92 ng / ml to 48.19±13.73 ng / ml, T 1 / 2 Five times that of ordinary atropine solution, C max It increased by 4 times.

[0132] Furthermore, in the atropine pharmaceutical composition of the present invention, the pharmacokinetic assay results are better when the content of atropine sulfate is 0.05% (as in the above-described formulation 17) compared to the formulation containing 0.01% atropine sulfate.

[0133] The embodiments described above are merely examples of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. An atropine pharmaceutical composition comprising a pharmaceutically acceptable salt of atropine, 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-based cation exchange resin is selected from one or two of sodium poly(divinylbenzene styrene) sulfonate and poly(divinylbenzene styrene) 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 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 pharmaceutically acceptable salts of the atropine is 0.005 to 1% (w / v), more preferably 0.008 to 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-based cation exchange resin to the pharmaceutically acceptable salt of the atropine is greater than or equal to 1, 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 also contains water, and the pH value of the atropine pharmaceutical composition is 5.0 to 6.

5.

9. The atropine pharmaceutical composition according to any one of claims 1 to 8, wherein, The atropine pharmaceutical composition also contains a pH adjuster 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 the total atropine is not more than 30 wt%, more preferably not more than 21 wt%, and even more preferably not more than 10 wt%.

11. The atropine pharmaceutical composition according to any one of claims 1 to 10, wherein, The total impurities and troponic acid impurities of the atropine drug composition after being stored at 60°C for 0 to 30 days are all less than 7 wt%, more preferably less than 6 wt%, even more preferably less than 4 wt%, and even more preferably less than 3 wt%.

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

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