Atropine pharmaceutical composition

Abstract

The present invention belongs to the field of pharmaceutical preparations and specifically 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, povidone, and hydroxyethylcellulose. The atropine pharmaceutical composition of the present invention can significantly reduce the free atropine content in the drug solution, thereby controlling the content of related substances within a low range, ensuring the drug has excellent stability at room temperature and achieving a better drug release effect.

Description

Technical Field

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

[0002] Ion exchange resins have long been widely used in a variety of fields, including chemical production, hydrometallurgy, atomic energy, food, pharmaceuticals, analytical chemistry, and environmental protection. With the cross-disciplinary development of these fields, ion exchange resins are increasingly being used as drug carriers in pharmacy, with several marketed products, such as dextromethorphan hydrobromide controlled-release suspension (Delsym), dihydrocodeine controlled-release suspension (Histions), and betaxolol hydrochloride eye drops (Betaxolol).

[0003] Ion exchange resins are classified by active groups 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 + ) are exchanged, so that B + Immobilized in the resin to form a complex. The use of cation exchange resin technology can achieve the purpose of masking the unpleasant taste of drugs, promoting dissolution or increasing bioavailability.

[0004] Due to their inherent properties, some chemical drugs are unstable during production and storage. For example, the atropine molecule contains small ester bonds, conjugated double bonds, and a toluene-like side chain structure, resulting in poor structural stability. During preparation, production, and long-term storage, it is prone to hydrolysis, oxidation, dehydration, and rearrangement reactions, producing corresponding alcohols, acids, or other intermediates. Conventional methods for improving stability include adjusting the pH value of the drug solution and lowering the storage temperature, but these methods are less than ideal or may result in inconvenience, poor patient compliance, and high costs.

[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” by synthesizing ophthalmic polystyrene sulfonate resin (SPSR) with spherical and uniform size to exchange cations 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, hydrochloric acid, remained undetectable at 40°C for 30 days. The levels of ATS 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 ) has increased significantly. In addition, the safety assessment confirmed that the ATS@SPSR suspension eye drops are 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) SPSR to achieve the drug loading capacity of ATS and the efficacy of ATS@SPSR suspension eye drops, but the SPSR that meets 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 determining the purity of atropine in this article is 225nm, while the more suitable wavelength for determining the purity of atropine is 210nm, so the separation of atropine and impurities by this method is poor, and the impurity results look better, but it is difficult to reflect the true purity of atropine. Summary of the Invention

[0006] The present invention aims to provide an atropine pharmaceutical composition, which contains atropine pharmaceutically acceptable salt, sulfonic acid cation exchange resin and 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 divinylbenzene) sulfonate (PSS) and poly(styrene divinylbenzene) 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 the 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 anhydroatropine 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 to 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 embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

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

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

[0023] Unless otherwise indicated, all terms (including technical and scientific terms) used to disclose the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. By way of further guidance, the following definitions are provided 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 herein include any one of two or more related listed items, and also include any and all combinations of the related listed items, wherein the arbitrary and all combinations include any combination of two related listed items, any more related listed items, or 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 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 of all being 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 four-item combination of A, B, C, and D (that is, the technical solution of all being 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] The recitation of numerical ranges herein by endpoints includes all numbers and fractions subsumed within the range, as well as the recited endpoints.

[0027] Concentration values ​​used in this invention include fluctuations within a certain range. For example, fluctuations within a certain precision range are permitted. For example, for 2%, fluctuations within ±0.1% are permitted. For larger values ​​or values ​​that do not require overly precise control, greater fluctuations are permitted. For example, for 100 mM, fluctuations within ±1%, ±2%, ±5%, etc. are permitted. Regarding molecular weight, fluctuations within ±10% are permitted.

[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, the terms "optionally," "optional," "optionally," "optionally," "optional," and "optional" mean optional or dispensable, i.e., they refer to either option being selected from two parallel options: "with" or "without." If multiple "optional" or "optional" terms appear in a technical solution, unless otherwise specified and there are no contradictions or constraints, each "optional" or "optional" term is independent of the others.

[0032] As used herein, the term "pharmaceutically acceptable salts of atropine" refers to certain salt forms of atropine used in pharmaceutical formulations that are pharmaceutically considered safe, effective, and suitable for use in formulations. Atropine is a widely used drug primarily used to treat various conditions, such as cardiac disorders, ophthalmic diseases, and certain poisoning conditions. In the present invention, the pharmaceutically acceptable salts of atropine specifically include salts of atropine that are acceptable for use in ophthalmic formulations.

[0033] As used herein, the term "sulfonic acid cation exchange resin" refers to a resin whose active group is a sulfonic acid group (-SO3H) that reacts with cations (positively charged ions). This type of resin is a polymeric material, typically 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 from 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 percentage by mass.

[0036] The present invention relates to an atropine pharmaceutical composition, which contains atropine pharmaceutically acceptable salt, 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).

[0037] The present invention first discovered that by loading a pharmaceutically acceptable salt of atropine onto a sulfonic acid cation exchange resin and adding the aforementioned suspending agent, the free atropine content in the solution can be significantly reduced, thereby slowing the overall degradation of atropine and improving the stability of the formulation. Furthermore, the aforementioned atropine pharmaceutical composition also exhibits 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 sodium poly(styrene divinylbenzene) sulfonate (PSS) and poly(styrene divinylbenzene) sulfonic acid (PSA). Both PSA and PSS have polystyrene polymer backbones, sulfonic acid groups as active groups, and exchangeable cations such as 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 selection of the above osmotic pressure regulators can further reduce the free atropine content 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 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 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 values, the loading capacity of atropine is slightly different, but as the dosage increases, the loading capacity 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, there is no particular restriction on the particle size of the sulfonic acid cation exchange resin. 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, with reference to the requirements of the 2020 edition of the Chinese Pharmacopoeia for ophthalmic preparations, the particle size should be controlled as follows: according to the particle size and particle size distribution determination method (General Rule 0982 First Method), there shall be no more than 2 particles larger than 50μm in each smear (except for those containing raw powder of decoction pieces), and no particles larger than 90μm shall be detected.

[0049] In some specific embodiments, the D90 of the sulfonic acid cation exchange resin is less than or equal to 40 μm, and the D50 is less than or equal to 20 μm. Sulfonic acid cation exchange resins that meet 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 to 10% (w / v).

[0051] In some preferred embodiments, the suspending agent is hydroxyethyl cellulose having a content of 0.1-2% (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 0.05-1% (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 the carbomer can be reduced to 0.05-0.2% (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 having 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 amount of the osmotic pressure regulator used in the present invention is not particularly limited. Those skilled in the art can adjust the amount of the osmotic pressure regulator based on the conditions of different osmotic pressure regulators to achieve an isotonicity of the atropine pharmaceutical composition with tears (260-320 mOsmol / kg). In some specific embodiments, the amount of the osmotic pressure regulator is 2.0-6.0% (w / v).

[0055] In some specific embodiments, the osmotic pressure regulator is mannitol having a content of 4.0-6.0% (w / v). As an example, the amount of 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 (260-320 mOsmol / kg). Those skilled in the art can also adjust the amount 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 2.0-3.0% (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. Therefore, theoretically, a pH value below 6.5 has good technical effects. Taking into account the comfort of ophthalmic medication, the pH value of the atropine pharmaceutical composition of the present invention is limited to 5.0 to 6.5.

[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 adjuster, wherein the pH adjuster is selected from one or more of hydrochloric acid, sodium hydroxide, and carbomer. The pH adjuster has no significant effect on the content of free atropine in the pharmaceutical solution.

[0061] In some embodiments, the content of free atropine in the atropine pharmaceutical composition is no more than 30wt%, more preferably no more than 21wt%, further preferably no more than 15wt%, further preferably no more than 13wt%, further preferably no more than 11wt%, further preferably no more than 10wt%, further preferably no more than 9wt%. The present invention also found 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. The lower the free atropine content, 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 even more preferably less than 3wt%.

[0063] In some embodiments, the content of anhydroatropine 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 0.10 wt%, more preferably less than 0.06 wt%, and further preferably 0 (i.e., not detected).

[0064] In some embodiments, the atropine pharmaceutical composition has an osmotic pressure of 260 to 320 mOsmol / kg. As an example, the osmotic pressure of the atropine pharmaceutical composition can be 260 mOsmol / kg, 270 mOsmol / kg, 280 mOsmol / kg, 290 mOsmol / kg, 300 mOsmol / kg, 310 mOsmol / 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 divinylbenzene) sulfonate or poly(styrene divinylbenzene) 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 of 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 uniformity of drug dispersion.

[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] The embodiments of the present invention will be described in detail below with reference to the examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. For experimental methods in the following examples where specific conditions are not specified, reference is made to the guidance provided in the present invention, and may also be made to experimental manuals or conventional conditions in the art, other experimental methods known in the art, or conditions recommended by the manufacturer.

[0073] In the following specific examples, 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 testing accuracy or operational accuracy are allowed.

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

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

[0076] Free atropine content assay: The sample was centrifuged at 15,000 rpm for 30 minutes, and the supernatant was diluted and injected. Octadecylsilane bonded silica gel (4.6 mm × 150 mm, 5 μm) was used as the filler, and the mobile phase consisted of 0.05 mol / L potassium dihydrogen phosphate solution (containing 0.0025 mol / L sodium heptanesulfonate, adjusted to pH 5.0 with phosphoric acid or sodium hydroxide solution)-acetonitrile (84:16) at a flow rate of 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, all references to free atropine content were based on the assay described herein.

[0077] The results are shown in Table 1 below, which show 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 loading capacity reaches equilibrium. The free content of atropine at different concentrations is basically consistent with the law of the amount of PSS / PSA used. PSS and PSA have slightly different atropine loading capacities due to different pH values, but as the dosage increases, the loading capacity 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 in the present invention is greater than or equal to 5.

[0078] Table 1

[0079]

[0080] The free content of the drug solution was determined using the same amount of PSA and PSS as cationic resins. The results showed no significant difference, 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 between exchangeable cations in the cation exchange resin and free cations in the 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 significant effect on the adsorption amount of atropine. In ophthalmic preparations, if the particle size of the inclusions is too large, there will be problems 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: according to the particle size and particle size distribution determination method (General Rule 0982 First Method), there shall be no more than 2 particles larger than 50μm in each smear (except for those containing raw powder of decoction pieces), and particles larger than 90μm shall not be detected. In order to facilitate the comparison of the effects, in all the prescriptions in the examples, PSS uses PSS of the same batch of uniform particle size, and its D50 is less than 10 microns; PSA uses PSA of the same batch of uniform particle size, and its D50 is less than 10 microns.

[0085] Table 3

[0086]

[0087] Example 3 Effect of suspending agent type and dosage

[0088] The addition of a suspending agent 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 impact of the type and amount of suspending agent in the composition. Each prescription component and dosage are shown in Table 4 below.

[0089] Table 4

[0090]

[0091] Viscosity was measured using a rotational viscometer, and sedimentation volume ratio was determined according to the method in the 2020 edition of the Chinese Pharmacopoeia. Redispersibility was determined by shaking the sample vigorously for 10 seconds after 24 hours. The suspension was transferred to a test tube and inspected for visible lumps in the suspension and the inner wall of the container. The results are shown in Table 5 below.

[0092] Using the main degradation product impurity A (anhydroatropine), impurity C (tropic acid), and total impurities as evaluation indicators, formulations 1, 15, and 16 were subjected to stability testing at high temperatures of 40°C and 60°C. Formulations with varying free atropine contents were examined. Related substance testing methods: Samples were treated with 1M potassium chloride solution (1:5 ratio) with stirring for 2 hours, centrifuged at 10,000 rpm for 10 minutes, and the supernatant was sampled for testing. Chromatographic conditions were the same as those for free atropine content. The results are shown in Table 6 below.

[0093] According to the test 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. 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, so it is not suitable to be used in large quantities in the prescription. Using it in combination 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. 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 sedimentation volume ratio and redispersibility requirements.

[0094] Table 5

[0095]

[0096] Table 6

[0097]

[0098]

[0099] Note: ND means not detected.

[0100] Example 4 Effect of pH Regulator Type

[0101] Adjusting the pH of a drug solution can affect its stability by introducing ions and causing changes in the free atropine content. This example 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 minimal cations and has no significant effect on the free atropine content. Therefore, the type and dosage of pH adjusters can be selected based on actual needs.

[0102] Table 7

[0103]

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

[0105] Ophthalmic preparations are used to adjust the osmotic pressure to a level similar to that of tears. This example compares the effects of the type of osmotic pressure regulator in the composition, using free atropine content as an indicator. See Table 8 below for specific formulations.

[0106] Table 8

[0107]

[0108]

[0109] Research results show that when sodium chloride, an ionic osmotic pressure regulator, is used to adjust osmotic pressure, the free atropine content in the solution is significantly higher than when glycerol and mannitol, non-ionic osmotic pressure regulators, are used. Therefore, non-ionic osmotic pressure regulators should be used, and the dosage should be adjusted to isotonicity with tear fluid (260-320 mOsmol / kg).

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

[0111] Atropine has a poor molecular structure and is prone to degradation during production and storage. High temperatures can exacerbate its degradation. Using the main degradation products, impurity A (anhydroatropine), impurity C (tropic acid), and total impurities as evaluation indicators, stability tests were conducted at 40°C and 60°C, examining formulations with varying free atropine contents.

[0112] Related substance detection methods:

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

[0114] Test solution: Take about 2.0g of this product, accurately weigh it, place it in a 25ml volumetric flask, add about 20ml of diluent, shake at 200 rpm for at least 20 minutes, dilute to the scale with diluent, shake well, centrifuge at 14,000 rpm for 15 minutes, and collect the supernatant. (0.04mg / ml)

[0115] Reference solution: Dissolve approximately 4 mg of atropine sulfate reference solution in a 100 ml volumetric flask, add diluent to dissolve and dilute to the mark, shake well; dissolve 1.0 ml in a 100 ml volumetric flask, dilute to the mark with diluent, and 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, dissolve them in diluent, and quantitatively dilute them to prepare 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: Use octadecylsilane bonded silica gel as the filler (2.1 mm × 100 mm, 3.5 μm or equivalent); use concentrated ammonia solution-water (1:100) (adjust the pH to 3.0 with perchloric acid) as mobile phase A, acetonitrile as mobile phase B, and perform gradient elution according to Table 9 below; flow rate, 0.4 ml per minute; column temperature, 30°C; detection wavelength, 210 nm; injection volume, 15 μl.

[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 the total impurities shall not exceed 7.0%. Therefore, the ratio of the free atropine content to the 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. Aside from the sodium poly(styrene divinylbenzene) sulfonate that forms the complex, formulations of varying concentrations can be prepared using the same excipient types and amounts. 0.05% and 0.01% solutions (Formulations 17 and 14) were prepared at a 1:5 (w:w) ratio of atropine sulfate to sodium poly(styrene divinylbenzene) sulfonate, respectively. These solutions were then subjected to stability studies alongside a standard atropine solution (Formulation 13) with sodium chloride as an osmotic pressure regulator and the same pH value. The specific formulations for each formulation are shown in Table 11, and the results are shown in Table 12 below. The osmotic pressure, viscosity, sedimentation volume ratio, and redispersibility of Formulations 14 and 17 were also tested. The results are shown in Table 11.

[0128] The test results show no significant differences in osmotic pressure, viscosity, sedimentation volume ratio, and redispersibility between Formulations 14 and 17, indicating that, with the exception of sodium poly(styrene divinylbenzene) sulfonate, the same type and amount of excipients can be used in formulations of varying concentrations. High-temperature stability results at 40°C show that the growth trend of impurity C and total impurities in Formulations 17 and 14 is significantly lower than that in Formulation 13, indicating good stability. This growth trend is sufficient for 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 its stability. Therefore, although Formula 13 contains 0.05% atropine sulfate, while some of the present invention's formulas contain 0.01% atropine sulfate, the present invention's formula, even with 0.01% atropine sulfate, still outperforms Formula 13, which contains 0.05% atropine sulfate. This comparison of effects is sufficient to demonstrate the significant stability advantage of the present invention's atropine pharmaceutical composition over conventional atropine solutions.

[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 formulation 17 using PSS technology and formulation 13 of ordinary atropine solution was tested using dynamic dialysis. Fresh simulated tear fluid (STF) was prepared and divided into 250 mL beakers, sealed with plastic wrap, and preheated in a constant temperature oscillator at 37°C ± 1°C. 8 cm of treated dialysis bag was cut, 4 mL of the test preparation was taken into the dialysis bag, and sealed with a sealing clip to ensure that the test preparation would not leak. The dialysis bag containing the test preparation was placed in the preheated dispersion medium and shaken at a speed of 50 rpm. 3 mL of the preparation was taken at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8 hours, respectively, and an equal amount of fresh STF solution was added.

[0137] See the results Figure 1 The results showed that the formulation 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] Tear pharmacokinetic testing was performed as follows: The pharmacokinetics of a formulation (Formulation 1) using PSS technology and a conventional atropine solution (0.01% strength, differing from Formulation 13 only in the presence of 0.01% atropine sulfate) were studied in the tears of New Zealand rabbits. Six New Zealand rabbits were instilled with Formulation 1 or a 0.01% conventional atropine solution into the left conjunctiva, 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 of atropine concentrations.

[0140] The pharmacokinetic assay for aqueous humor was performed as follows: Six rabbits were randomly divided into two groups and administered prescription 1 eye drops (n=3) or regular atropine solution (0.01%) eye drops (n=3). Aqueous humor samples were collected for atropine content 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 was 0-t and C max They are 6.4 times and 2.2 times that 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 Increased from 21.04±5.76ng·h / ml to 126.44±27.22ng·h / ml, C max Increased 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 formulation containing 0.01% atropine sulfate, when the content of atropine sulfate is 0.05% (such as the above-mentioned formulation 17), the pharmacokinetic detection effect is better.

[0147] The above-described embodiments merely illustrate several implementations of the present invention. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, and all such variations and improvements fall within the scope of protection of the present invention.

Claims

1. An atropine pharmaceutical composition, which is composed of a pharmaceutically acceptable salt of atropine, a sulfonic acid cation exchange resin, a suspending agent, an osmotic pressure regulator, a pH regulator and a solvent. in, The suspending agent is selected from one or more of povidone and hydroxyethyl cellulose; The sulfonic acid cation exchange resin is selected from one or both of sodium poly(styrene divinylbenzene) sulfonate and poly(styrene divinylbenzene) sulfonic acid; The pharmaceutically acceptable salt of atropine is atropine sulfate; The osmotic pressure regulator is selected from one or both of glycerol and mannitol; 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 content of free atropine in total atropine is not higher than 30 wt%.

2. The atropine pharmaceutical composition according to claim 1, wherein The content of the pharmaceutically acceptable salt of atropine is 0.005-1% w / v.

3. The atropine pharmaceutical composition according to claim 2, wherein The content of the pharmaceutically acceptable salt of atropine is 0.008-0.05% w / v.

4. The atropine pharmaceutical composition according to any one of claims 1 to 3, wherein The content of the suspending agent is 0.01-10% w / v.

5. The atropine pharmaceutical composition according to claim 4, wherein The suspending agent is hydroxyethyl cellulose with a content of 0.1-2% w / v or povidone with a content of 1-10% w / v.

6. The atropine pharmaceutical composition according to any one of claims 1 to 3 and 5, wherein The solvent is water, and the pH value of the atropine pharmaceutical composition is 5.0-6.

5.

7. The atropine pharmaceutical composition according to claim 4, wherein The solvent is water, and the pH value of the atropine pharmaceutical composition is 5.0-6.

5.

8. The atropine pharmaceutical composition according to any one of claims 1 to 3, 5, and 7, wherein The pH regulator is selected from one or more of hydrochloric acid and sodium hydroxide.

9. The atropine pharmaceutical composition according to claim 4, wherein The pH regulator is selected from one or more of hydrochloric acid and sodium hydroxide.

10. The atropine pharmaceutical composition according to claim 6, wherein The pH regulator is selected from one or more of hydrochloric acid and sodium hydroxide.

11. The atropine pharmaceutical composition according to claim 1, wherein The content of free atropine in total atropine is not higher than 21wt%.

12. The atropine pharmaceutical composition according to claim 1, wherein The content of free atropine in total atropine is not higher than 10wt%.

13. The atropine pharmaceutical composition according to claim 1, wherein The atropine pharmaceutical composition has a total impurity content and a tropine acid impurity content of less than 7 wt % after being stored at below 60° C. for 0 to 30 days.

14. The atropine pharmaceutical composition according to claim 1, wherein The atropine pharmaceutical composition has a total impurity content and a tropine acid impurity content of less than 6 wt % after being stored at below 60° C. for 0 to 30 days.

15. The atropine pharmaceutical composition according to claim 1, wherein The atropine pharmaceutical composition has a total impurity content and a tropine acid impurity content of less than 4 wt % after being stored at below 60° C. for 0 to 30 days.

16. The atropine pharmaceutical composition according to claim 1, wherein The atropine pharmaceutical composition has a total impurity content and a tropine acid impurity content of less than 3 wt % after being stored at below 60° C. for 0 to 30 days.

17. The atropine pharmaceutical composition according to claim 1, wherein The osmotic pressure of the atropine pharmaceutical composition is 260-320 mOsmol / kg.

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