Multi-chamber container for eye drops and method of manufacturing the same

Abstract

The present invention provides a multi-chamber container for storing and administering eye drops, the container having at least two chambers completely separated by a separable sealing portion, each chamber independently containing a different type of drug, thereby preventing changes over time when these drugs are mixed together. The sealing portion of the container of the present invention can be separated by applying an external force to one of the chambers of the container, thereby allowing the independently enclosed different drugs to mix together under sterile conditions and form a mixed solution that can be administered directly to the eye. The present invention also provides a method for manufacturing such a multi-chamber container.

Description

[Technical Field]

[0001] The present invention relates to a container for storing and dispensing eye drops, and further to a method for manufacturing such a multi-chamber container. [Background technology]

[0002] The pH range of drugs tolerated by the human eye is 5.0 to 9.0, and eye drops generally fall within this range. Eye drops with a pH below 5.0 or above 11.4 can cause significant eye irritation. However, within this pH range, some active ingredients in common eye drops exhibit instability due to susceptibility to hydrolysis. For example, drugs with easily hydrolyzed ester or amide bonds. In particular, for children and adolescents with high myopia, ocular discomfort after administration often leads to relatively poor compliance. To reduce eye irritation, currently available eye drop products still use solution pHs that are unfavorable for stable storage and are therefore unsuitable for long-term storage.

[0003] Containers with multiple chambers are already used to contain medical mixed solutions that are unstable over time. One type of container utilizes a separable sealing member to form an isolation structure. The separable sealing member can be ruptured by tension or by compressing the adjacent liquid-filled container chamber. Multi-chamber containers with separable sealing members can form larger openings to facilitate thorough mixing of the solutions. However, only flexible bags made of highly elastic and heat-resistant film materials have been reported for such containers (see CN1976668A). There are several common problems that must be solved for such flexible multi-chamber infusion bags. First, the separable sealing member may be improperly opened by unavoidable external forces during transportation or other processes before it reaches the intended user. Second, after it safely reaches the intended user, the separable sealing member is difficult to open, preventing the formation of the desired mixed solution. According to reports, for flexible medical injection bags with multiple chambers, the seals are preferably separated by a pulling or rolling method to mix the contents. However, even professionally trained clinicians or caregivers cannot guarantee that most flexible containers with separable seals can be opened easily and safely, and ordinary people (especially the elderly, children, and individuals with hand disabilities or muscle weakness) usually cannot use them independently without the aid of special tools. Third, due to the film material and opening method, such flexible bags are not suitable for filling relatively small amounts of medical liquid, and are often used in a disposable manner. Therefore, in the field of eye drops, which require drop-by-drop administration, the currently commonly used container is still a single-chamber eye drop bottle made of a material such as plastic that has a certain degree of rigidity.

[0004] Prior art multi-chamber containers also exist, where the chambers are separated by separators made of rigid, easily crushable materials. While the advantage of such multi-chamber containers is their high versatility, the separators often only allow for limited cutout cross-sections, which is detrimental to adequate mixing of the solutions, and breakage of the separators can result in the mixed solution containing a significant increase in the number of undesirable particles (see EP 0 378 183 ). Increased insoluble particles are particularly associated with discomfort during use of ophthalmic solutions and may even lead to non-compliance with mandatory standards related to eye drops. Summary of the Invention

[0005] An object of the present invention is to provide an eye drop container which has at least two chambers separated from each other by a separable sealing member and which can be easily and reliably opened by an ordinary person without professional training without the aid of any special tools, thereby not only ensuring the stability of the contained ophthalmic solution at low or high pH but also effectively avoiding discomfort caused by non-physiological pH and irritation to the human eye due to insoluble particles.

[0006] In order to solve the above problems, the present invention provides a multi-chamber container for eye drops, characterized in that the container body comprises two or more chambers including at least a first chamber and a second chamber, the first chamber communicates with an outlet, the remaining chambers are connected to the first chamber or other chambers, adjacent chambers are separated by a sealing portion (2) and do not communicate with each other, and when an external force is applied to the outer wall of one of the two adjacent chambers, the sealing portion between the two adjacent chambers is irreversibly separated, and when all the sealing portions are separated, each chamber communicates directly or indirectly with the first chamber.

[0007] According to the multi-chamber container of the present invention, the outlet is further provided with a seal cap that can be opened only once or repeatedly opened and closed.

[0008] According to the multi-chamber container of the present invention, the container body is made of a rigid plastic material.

[0009] According to the multi-chamber container of the present invention, the multi-chamber container is composed of two chambers.

[0010] According to the above multi-chamber container of the present invention, the above-mentioned sealed portion is formed by pre-welding the container body using ultrasonic waves, with the torque strength of the electric cylinder being 232-266 Newtons and the welding time being 0.290-0.370 s.

[0011] According to the multi-chamber container of the present invention, the sealed portion is formed by pre-welding the container body using ultrasonic waves having an amplitude of 10% to 42% and a welding time of 0.19 to 0.64 seconds, preferably ultrasonic waves having an amplitude of 36% to 39% and a welding time of 0.47 to 0.49 seconds.

[0012] According to the multi-chamber container of the present invention, the external force that can irreversibly separate the sealed portions does not exceed the average grip strength of the fingers of a 5-7 year old child, preferably about 17-27 Newtons (N).

[0013] According to the above multi-chamber container of the present invention, the heat seal strength of the sealed portion (2) is 3 Newtons or more, 5 Newtons or more, 7 Newtons or more, 10 Newtons or more, 12 Newtons or more, 14 Newtons or more, or 16 Newtons or more, and 62 Newtons or less, 60 Newtons or less, 58 Newtons or less, 55 Newtons or less, 51 Newtons or less, 45 Newtons or less, 40 Newtons or less, 38 Newtons or less, 34 Newtons or less, or 30 Newtons or less, preferably 3 to 60 Newtons, 5 to 58 Newtons, 7 to 58 Newtons, 10 to 55 Newtons, 12 to 51 Newtons, or 16 to 38 Newtons.

[0014] For example, in different forms, the heat seal strength of the sealing portion (2) is 3 Newtons or more and 62 Newtons or less, 3 Newtons or more and 60 Newtons or less, 3 Newtons or more and 58 Newtons or less, 3 Newtons or more and 55 Newtons or less, 3 Newtons or more and 51 Newtons or less, 3 Newtons or more and 45 Newtons or less, 3 Newtons or more and 40 Newtons or less, 3 Newtons or more and 38 Newtons or less, 3 Newtons or more and 34 Newtons or less, or 3 Newtons or more and 30 Newtons or less, and for example, in different forms In the present invention, the heat seal strength of the sealing portion (2) is 5 Newtons or more and 62 Newtons or less, 5 Newtons or more and 60 Newtons or less, 5 Newtons or more and 58 Newtons or less, 5 Newtons or more and 55 Newtons or less, 5 Newtons or more and 51 Newtons or less, 5 Newtons or more and 45 Newtons or less, 5 Newtons or more and 40 Newtons or less, 5 Newtons or more and 38 Newtons or less, 5 Newtons or more and 34 Newtons or less, or 5 Newtons or more and 30 Newtons or less, and for example, in a different form, the sealing portion (2) The heat seal strength of the sealing portion (2) is 7 Newtons or more and 62 Newtons or less, 7 Newtons or more and 60 Newtons or less, 7 Newtons or more and 58 Newtons or less, 7 Newtons or more and 55 Newtons or less, 7 Newtons or more and 51 Newtons or less, 7 Newtons or more and 45 Newtons or less, 7 Newtons or more and 40 Newtons or less, 7 Newtons or more and 38 Newtons or less, 7 Newtons or more and 34 Newtons or less, or 7 Newtons or more and 30 Newtons or less, and for example, in a different embodiment, the heat seal strength of the sealing portion (2) is , 10 Newtons or more and 62 Newtons or less, 10 Newtons or more and 60 Newtons or less, 10 Newtons or more and 58 Newtons or less, 10 Newtons or more and 55 Newtons or less, 10 Newtons or more and 51 Newtons or less, 10 Newtons or more and 45 Newtons or less, 10 Newtons or more and 40 Newtons or less, 10 Newtons or more and 38 Newtons or less, 10 Newtons or more and 34 Newtons or less, or 10 Newtons or more and 30 Newtons or less, and for example, in a different embodiment, the heat seal strength of the sealing portion (2) is12 Newtons or more and 62 Newtons or less, 12 Newtons or more and 60 Newtons or less, 12 Newtons or more and 58 Newtons or less, 12 Newtons or more and 55 Newtons or less, 12 Newtons or more and 51 Newtons or less, 12 Newtons or more and 45 Newtons or less, 12 Newtons or more and 40 Newtons or less, 12 Newtons or more and 38 Newtons or less, 12 Newtons or more and 34 Newtons or less, or 12 Newtons or more and 30 Newtons or less, and for example, in different embodiments, the heat seal strength of the sealing portion (2) is 14 Newtons or more and 62 Newtons or less, 14 Newtons or more and 60 Newtons or less, 14 Newtons or more and 58 Newtons or less, 14 Newtons or more and 55 Newtons or less, 14 Newtons or more and 51 Newtons or less, 14 Newtons or more and 30 Newtons or less, and Newtons or more and 45 Newtons or less, 14 Newtons or more and 40 Newtons or less, 14 Newtons or more and 38 Newtons or less, 14 Newtons or more and 34 Newtons or less, or 14 Newtons or more and 30 Newtons or less; and for example, in different embodiments, the heat seal strength of the sealing portion (2) is 16 Newtons or more and 62 Newtons or less, 16 Newtons or more and 60 Newtons or less, 16 Newtons or more and 58 Newtons or less, 16 Newtons or more and 55 Newtons or less, 16 Newtons or more and 51 Newtons or less, 16 Newtons or more and 45 Newtons or less, 16 Newtons or more and 40 Newtons or less, 16 Newtons or more and 38 Newtons or less, 16 Newtons or more and 34 Newtons or less, or 16 Newtons or more and 30 Newtons or less.

[0015] According to the multi-chamber container of the present invention, the container further includes a container tail portion (7). In some embodiments, the tail portion is formed under sealing conditions of a cylinder air pressure of 2.0 to 2.5 bar and a welding time of 0.16 to 0.22 seconds. In other embodiments, the tail portion is formed under sealing conditions of an ultrasonic amplitude of 43% or more and a welding time of 0.65 seconds or more. The tail portion is intended to form a break-resistant closure in the multi-chamber container of the present invention.

[0016] According to the multi-chamber container of the present invention, the container body is tubular.

[0017] According to the multi-chamber container of the present invention, the tubular member has a length of 15 to 180 mm and an inner diameter of 4 to 30 mm.

[0018] According to the multi-chamber container of the present invention, the thickness of the rigid plastic forming the container is 200 to 2000 μm, preferably 350 to 500 μm, and more preferably 380 to 400 μm.

[0019] According to the multi-chamber container of the present invention, the container has a capacity of 0.2 mL or more and 20 mL or less.

[0020] The present invention further provides an eye drop product in which different drugs are filled in the multiple chambers of the multi-chamber container, at least one of the drugs having a pH value lower than about 5.3 or higher than about 8.3, a mixed solution formed by mixing the drugs filled in the multiple chambers having a pH value of about 5.3 to about 8.3, and the stability (e.g., hydrolytic stability) of the at least one drug is higher than the stability of the mixed solution formed after mixing the drugs filled in the different chambers.

[0021] The present invention further provides a method for producing the above-described ophthalmic solution product, the method comprising: selecting a material suitable for manufacturing into a container body, the material having a hollow structure with both ends open or open; forming an outlet communicating with the first chamber at an opening at one end of the hollow structure, and preferably providing the outlet with a seal cap that can be opened once or repeatedly opened and closed; filling the hollow structure at the other end opening with a first predetermined volume of a first medicament when the outlet is in a closed state; tack-welding the hollow structure at a location corresponding to the first predetermined volume to form a separable sealed portion, thereby forming a sealed first chamber between the separable sealed portion and the outlet, the first agent contained therein; continuing to fill a second chamber formed between the opening and the separable sealing portion with a second predetermined volume of a second medicament, different from the first medicament, through the opening at the other end; By this analogy, optionally forming more chambers filled with more different drugs separated from each other by sealing portions; filling the last chamber with the last drug and then sealing the last chamber by welding to form the container tail; Including, This allows the various drugs filled in each chamber to eventually mix with the drug in the first chamber directly or indirectly by separating from each sealed portion, and then be discharged from the outlet.

[0022] According to the method for producing an ophthalmic solution product of the present invention, the above-mentioned sealed portions are formed by temporary welding using ultrasonic waves with an electric cylinder torque strength of 232-266 Newtons and a welding time of 0.290-0.370 seconds, and the container tail portion is formed by welding and sealing the last chamber using ultrasonic waves with a cylinder pressure of 2.0-2.5 bar and a welding time of 0.16-0.22 seconds.

[0023] According to the method for producing an eye drop product of the present invention, the above-mentioned sealed portions (2) are formed by temporary welding using ultrasonic waves with an amplitude of 10% to 42% and a welding time of 0.19 to 0.64 seconds, preferably ultrasonic waves with an amplitude of 36% to 39% and a welding time of 0.47 to 0.49 seconds, and the container tail portion (7) is formed by welding and sealing the last chamber under sealing conditions of an amplitude of 43% or more and a welding time of 0.65 seconds or more.

[0024] According to the method for producing an eye drop product of the present invention, the material of the container body is a rigid plastic.

[0025] According to the method for producing an eye drop product of the present invention, the multi-chamber container is composed of two chambers.

[0026] According to the method for producing the ophthalmic solution product of the present invention, the external force that can irreversibly separate the above-mentioned sealed portion does not exceed the average grip strength of the fingers of a child aged 5 to 7, and preferably does not exceed about 17 to 27 Newtons (N).

[0027] According to the method for producing an ophthalmic solution product of the present invention, the heat seal strength of the sealed portion (2) is 3 Newtons or more, 5 Newtons or more, 7 Newtons or more, 10 Newtons or more, 12 Newtons or more, 14 Newtons or more, or 16 Newtons or more, and 62 Newtons or less, 60 Newtons or less, 58 Newtons or less, 55 Newtons or less, 51 Newtons or less, 45 Newtons or less, 40 Newtons or less, 38 Newtons or less, 34 Newtons or less, or 30 Newtons or less, preferably 3 to 60 Newtons, 5 to 58 Newtons, 7 to 58 Newtons, 10 to 55 Newtons, 12 to 51 Newtons, or 16 to 38 Newtons. Specific ranges of the heat seal strength of the sealed portion (2) are the same as those described above, and therefore will not be listed one by one.

[0028] According to the method for producing an eye drop product of the present invention, the container body is tubular.

[0029] According to the method for producing an eye drop product of the present invention, the tubular product has a length of 15 to 180 mm and an inner diameter of 4 to 30 mm.

[0030] According to the method for producing an ophthalmic solution product of the present invention, the thickness of the rigid plastic is 200 to 2000 μm, preferably 350 to 500 μm, and more preferably 380 to 400 μm.

[0031] According to the method for producing an eye drop product of the present invention, the multi-chamber container has a volume of 0.2 mL or more and 20 mL or less.

[0032] The multi-chamber container or eye drop product of the present invention can achieve the following excellent effects:

[0033] 1. Because the different chambers are isolated from each other before use, some drugs that are difficult to store can be stored in a relatively suitable environment before use. By temporarily mixing them at the time of use, the final formulation can be made suitable for use, thereby increasing compliance and extending the shelf life of the drug.

[0034] 2. The tack-welded structure of the present invention can stably separate the different chambers, and the structure remains stable even under general external forces during production, transportation, storage, sales, etc., and can be easily pinched open from the outside by anyone, from children to the elderly, without the need for special tools. The sealed environment inside the container is not destroyed during the pinch-opening process, ensuring a sterile environment, and even the small amount of insoluble particles produced after pinch-opening will not destroy the quality of the drug.

[0035] 3. The container of the present invention has a small overall volume, with a total loading volume of approximately 20 mL or less, and is primarily used as a container for medical solutions with relatively small usage volumes, such as eye drops. The loading volume of the container of the present invention can be a single dose or can meet the requirements for multiple doses (usually not exceeding one month's dose). Due to its low dosage and good sealing properties, the container of the present invention can still meet the relevant requirements of pharmaceuticals without the need to add bacteriostatic agents such as benzalkonium chloride. This avoids the irritation caused by bacteriostatic substances to human organs, especially sensitive organs such as the eyes. [Brief explanation of the drawings]

[0036] [Figure 1]FIG. 1 shows an example of a multi-chamber eye drop container according to the present application. In the figure, 1 denotes the container body, 2 denotes a temporary welded seam, 3 denotes a first chamber, 4 denotes a second chamber, 5 denotes an outlet, 6 denotes a seal cap, and 7 denotes a container tail. [Figure 2] 1 illustrates a sample for heat seal strength measurement manufactured using the dual chamber container disclosed in the present specification, and a heat seal strength measurement test, in which 8 is an upper jig, 9 is a lower jig, 10 is a strip manufactured from the container body, 11 is the width of the tack weld seam, and 12 is the length (W) of the tack weld seam of the sample. DETAILED DESCRIPTION OF THE INVENTION

[0037] The container of the present invention will be further described below with reference to the drawings and specific embodiments. The described examples are merely for the purpose of clarifying the present invention and are not intended to limit the scope of the present invention. The examples provided below may serve as a guide for those skilled in the art to make further improvements and are not intended to limit the present invention in any way. As used herein, the terms "comprise" or "comprises" mean that the structures and processes include the described components or steps but do not exclude other components or steps. As used herein, the term "about" refers to a general error range for the corresponding value that is readily known to those skilled in the art. In this specification, a value or parameter described as "about" includes the value or parameter itself.

[0038] The term "multi-chamber" or "plurality of chambers" refers not only to the two-chamber case illustrated in the specific embodiment, but also to more chambers, for example, three or more chambers, that can be easily conceived by a person skilled in the art based on the contents disclosed in the present invention and specific needs.

[0039] The term "rigid plastic" as used herein refers to a plastic that can be deformed by external force, such as pinching with fingers, and automatically return to its original shape after the external force is removed. For example, it refers to a typical plastic material used for single-dose or multi-dose eye dropper bottles (see "9621 Guiding Principles for General Requirements for Drug Packaging Materials" in the Four General Provisions of the Chinese Pharmacopoeia 2015 Edition, and "National Drug Packaging Materials Standards," edited by the China Academy of Food and Drug Certification, China Pharmaceutical Science and Technology Publishing House). In other words, the plastic used to manufacture the container of the present invention may be any known plastic in the art that is suitable for manufacturing single-dose or multi-dose medical solution bottles, as long as its elastic modulus is sufficient to achieve the reversible deformation and recovery of the present invention. Non-limiting examples of rigid plastics used in the present invention include polyolefin resins, including, but not limited to, polyethylene-based resins such as low-density polyethylene, polypropylene-based resins such as polypropylene, cyclic polyolefin resins, and composite layer materials incorporating different polyolefins. For the rigid plastics used in the present invention, further reference may be made to, for example, the "Manual for Rapid Inspection of Commonly Used Plastic Varieties" edited by Takaaki Sai et al. Non-limiting examples of the "rigid plastics" in the present invention may further be referred to the examples described in the patent application for invention entitled "Low Concentration Atropine Drug Product and Manufacturing Method Thereof," filed by the applicant on the same day as the filing date of this application. This application is incorporated herein by reference in its entirety.

[0040] In one aspect of the present invention, the thickness of the rigid plastic used in the container of the present invention is such that it not only achieves the reversible deformation and recovery required for the container of the present invention, but also has the mechanical strength required for a pharmaceutical container (particularly an eye drop container). In a preferred embodiment, the rigid plastic used in the container of the present invention has a thickness of 200 to 2000 μm, preferably 350 to 500 μm, and more preferably 380 to 400 μm. When it is necessary to block oxygen, water vapor, light, or illumination, the resin used in the container of the present invention may be laminated with a metal material such as aluminum foil. In this case, the thickness of the rigid plastic of the container of the present invention is the thickness after all laminated materials are included.

[0041] In one aspect of the present invention, the container of the present invention may be of any suitable shape as long as it is suitable for containing a single dose or multiple doses of a pharmaceutical solution. In a preferred embodiment, the container of the present invention is made of a tubular, rigid plastic having a certain length and diameter. As used herein, "tubular" refers to a hollow, columnar structure having a certain length. In some embodiments, the length of the tubular structure is significantly greater than its diameter. In a preferred embodiment, the tubular structure has a length of 15 to 180 mm and an inner diameter of 4 to 30 mm.

[0042] In one aspect of the present invention, the container of the present invention has a capacity suitable for containing a single dose or multiple doses of a pharmaceutical solution. As used herein, "capacity" refers to the total volume of solution that can be contained in all chambers contained in the container. In some embodiments, the container of the present invention has a capacity of 0.2 mL or more and 20 mL or less.

[0043] The approximate relationship between capacity and pipe size is as follows:

[0044] [Table 1]

[0045] In one aspect of the present invention, the term "separable sealing component" can be used interchangeably with "tack weld seam" and primarily refers to a structure formed by a tack welding process on the container body of the present invention, which can isolate different chambers of the container of the present invention and can be peeled or separated with a certain force. The tack weld seam of the container of the present invention can be applied to any design as long as it can be easily separated by pressure applied to one of the chamber walls by a user for use, and does not cause undesired separation due to normal external forces during the manufacturing, packaging, transportation, sale, etc. In some embodiments, the tack weld seam may have an elongated, linear structure. In other embodiments, the tack weld seam may have an arc shape with a bend or an intersecting straight shape with an included angle. In some embodiments, the tack weld seam has a uniform and equal width. In other embodiments, the tack weld seam has a variable width. In a preferred embodiment, the width of the tack weld seam is 1 to 20 mm, preferably 2 to 8 mm, and more preferably 4 mm. When describing a sealing component, the term "width" refers to the length that the component occupies along the longitudinal axis of the container.

[0046] In one embodiment of the present invention, the multiple chambers of the container of the present invention are each filled with a different medical solution. For example, if the container of the present invention has two chambers, the first chamber may be filled with a drug that is easily hydrolyzed, and the second chamber may be filled with an aqueous solution of pharmaceutically acceptable auxiliary ingredients. Non-limiting examples of drugs that can be filled in the first chamber include ester-based drugs such as tetracaine hydrochloride, cocaine hydrochloride, propantheline, atropine sulfate, and homatropine hydrobromide, as well as amide-based drugs. Non-limiting examples of drugs that can be filled in the second chamber include, but are not limited to, buffer salts, osmotic pressure adjusting agents, preservatives, and / or metal ion chelators. Those skilled in the art will understand that the contents of the chambers of the container of the present invention can be changed, and that, for example, the solutions in the two chambers can be replaced with other suitable solutions, as long as they can be ultimately mixed to form an eye drop that can be administered directly to the eye. For example, the ester-based drug in the first chamber may be replaced with a lactone-based drug such as pilocarpine nitrate or warfarin sodium. In another embodiment of the invention, the distribution of the filling solutions to the container chambers can also be varied, i.e., the first chamber can contain an aqueous solution of a pharmaceutically acceptable adjuvant, such as a buffer, and the second chamber can contain a hydrolysis-sensitive drug solution. In another embodiment of the invention, the user should homogeneously mix the two solutions immediately prior to administration to form an eye drop solution for administration directly to the eye.

[0047] In one embodiment of the present invention, the outlet and seal cap used in the container of the present invention may have any outlet and seal cap structure commonly used in this field, as long as the solution located in the container can be squeezed out drop by drop from the container when the seal cap is opened. In another embodiment of the present invention, the outlet of the container of the present invention may be a closed port that does not require a cap, as long as it can be easily opened when used. In another embodiment of the present invention, the outlet of the container of the present invention may further be a seal cap that can be repeatedly opened and closed and that can be attached and detached to the multi-chamber container body.

[0048] In one embodiment of the present invention, the position of the tack weld can be easily determined depending on the amount of target solution to be injected. For example, if two target solutions are injected in equal amounts, the tack weld is performed near the midpoint of the container body. In a specific embodiment, the process for tack welding the container of the present invention preferably uses ultrasonic welding, but other appropriate welding methods may be selected. Non-limiting examples of tack welding include using an ultrasonic welding machine (model number STD20-1500W) with an electric actuator model number LEYH32NZC-50M, or an ultrasonic welding machine with an ultrasonic generator model number EDG-2020.

[0049] In one embodiment of the present invention, the process for sealing the tail portion is a process commonly used in the field for welding plastic materials, including, but not limited to, heat welding, ultrasonic welding, etc. In a preferred embodiment of the present invention, the tail portion of the container of the present invention is sealed using ultrasonic welding. Non-limiting examples of sealing the tail portion include using an ultrasonic welding machine (model number STD-2000W) with a cylinder model number MD81840-50Z, or an ultrasonic welding machine with an ultrasonic generator model number EDG-2020.

[0050] In the following examples, similar or like parts are designated by similar reference numerals and will not be described repeatedly.

[0051] Example 1: Container structure, composition and usage FIG. 1 shows a specific embodiment of the present application.

[0052] The multi-chamber container body 1 includes a first chamber 3 and a second chamber 4. Between the first chamber 3 and the second chamber 4 is a sealed portion 2 (ie, a tack welded seam).

[0053] The material of the container body 1 is polyolefin resin, which allows temporary welding using an ultrasonic process, and which has transparency, hygiene, and appropriate elasticity and rigidity.

[0054] During administration, no special auxiliary device is required. For example, by manually applying pressure with one hand to the first chamber 3 or the second chamber 4 to increase the internal pressure of the chamber, the tack welded seam is opened, and the first chamber 3 and the second chamber 4 are connected to each other, allowing the pharmaceutical solutions contained in the two chambers to mix. Furthermore, the manual application of pressure prevents damage to the tail portion 7 of the multi-chamber container, preventing the contents of the container from undesirably leaking out of the tail portion. Next, the seal cap 6 at the tip of the outlet 5 is unscrewed and removed, opening the outlet 5, allowing the formed mixed solution to be squeezed out drop by drop from the outlet 5.

[0055] Example 2: Manufacturing of a multi-chamber ophthalmic solution product The multi-chamber eye drop product of the present invention can be manufactured by the following process.

[0056] The dual chamber vessel body was fabricated using a low density polyethylene (LDPE) hose with a diameter of 13.0 mm (±0.2 mm) and open ends.

[0057] First, the polyolefin hose was cut into short pieces of uniform length. The specific length can be adjusted appropriately depending on the amount of drug to be loaded, but was generally about 40 mm or more. In this example, the hose was cut to a length of 40 mm.

[0058] Thereafter, a conventional blow molding process was used to form an outlet 5 at one end of the cut hose, which communicated with the chamber in the container body. The container was further provided with a seal cap 6 that fitted onto the outlet 5 to close the outlet.

[0059] The first chemical solution was injected into the container body 1 from the other end of the hose where no outlet was formed. After that, ultrasonic tack welding was performed at the midpoint of the length of the container body 1 using an ultrasonic welding machine with model number STD20-1500W having an electric actuator with model number LEYH32NZC-50M, and the welding time was 0.290 to 0.370 seconds.

[0060] After the tack welding, the container body 1 had two chambers that were not connected to each other: a first chamber 3 with an outlet 5, and a second chamber 4 that was spaced from the outlet 5 and connected to the first chamber 3 by tack welding. Of these, the first chamber 3 was already filled with the first type of medicinal solution, and the other was a hollow structure that still contained no solution.

[0061] The second type of medicinal solution was then filled into the container body 1 through the opening of the hollow structure, and the opening was then closed by welding using an ultrasonic welding machine, model number STD-2000W, which had a cylinder, model number MD81840-50Z, to form the container tail portion 7, thereby forming a closed second chamber 4 filled with the second type of medicinal solution.

[0062] In this example, the complete sealing rate was tested when the container tail was sealed using different manufacturing parameters, including a cylinder air pressure of 1.7 to 2.5 bar and a welding time of 0.16 to 0.22 seconds. The results are shown in Table 2 below.

[0063] [Table 2]

[0064] In this example, the torque strength of the electric cylinder was set to 232-266 N, and the welding time was set to 0.200-0.370 s. The test was conducted to determine the complete sealing rate and the pinch-open rate of the containers with the tack welded seams sealed. The results are shown in Table 3 below, based on measurements using conventional equipment.

[0065] [Table 3]

[0066] Under conditions simulating everyday use, six children (average age 7), six young adults (average age 28), and six elderly people (average age 60) independently pinched open 15 eye drop bottles. The average time required for each subject to completely pinch open the tack welded seam of the eye drop bottle was measured and is shown in Table 4 below. In the table, Group A represents tack welding for a welding time of 0.345 seconds with a cylinder torque strength of 238.6 Newtons, while Group B represents tack welding for a welding time of 0.305 seconds with a cylinder torque strength of 241 Newtons.

[0067] [Table 4]

[0068] As can be seen from Table 4, changing the tack-welding conditions has some effect on the time required for subjects to pinch open the container of the present invention. However, generally speaking, the tack-welded seam of the dual-chamber container of the present invention can be easily opened by general users without specialized training to perform subsequent eye-drop administration. Furthermore, even children and elderly people, who have relatively weaker fine manipulation ability and grip strength, can easily and quickly pinch open the container of the present invention.

[0069] Example 3: Manufacturing of a multi-chamber ophthalmic solution product The multi-chamber ophthalmic solution of the present invention can also be produced by the following process.

[0070] The polyolefin hose was subjected to outlet molding, filling with the first solution, temporary welding, filling with the second solution, and tail sealing in the same order as in Example 2. Unlike Example 2, the polyolefin hose used in this example was a polypropylene hose, and temporary welding and tail sealing were completed using the same ultrasonic welding equipment by changing the amplitude and welding time of the ultrasonic generator (model number EDG-2020).

[0071] In this example, the complete sealing rate was tested when the container tail was sealed using different manufacturing parameters, with the amplitude ranging from 10% to 45% and the welding time ranging from 0.19 to 0.95 seconds. The results are shown in Table 5 below.

[0072] [Table 5]

[0073] In this example, the complete sealing rate and the pinch-open rate of the containers were tested by using different manufacturing parameters, such as an amplitude of 10% to 45% and a welding time of 0.19 to 1.10 seconds, to seal and form the tack welded seams. The results are shown in Table 6 below, based on measurements using conventional equipment.

[0074] [Table 6]

[0075] Under conditions simulating everyday use, six children (average age 7), six young adults (average age 28), and six elderly people (average age 60) independently pinched open 15 eye drop bottles. The average time required for each subject to completely pinch open the tack-welded seam of the eye drop bottle was measured and is shown in Table 7 below. In the table, Group A represents tack-welded seams with a welding time of 0.47 seconds and an amplitude of 39%, while Group B represents tack-welded seams with a welding time of 0.49 seconds and an amplitude of 36%.

[0076] [Table 7]

[0077] As can be seen from Table 7, changing the tack welding conditions does have some effect on the time required for subjects to pinch open the container of the present invention. However, generally speaking, the tack weld seam of the dual chamber container of the present invention can be easily opened by a general user without specialized training.

[0078] Example 4: Measurement of insoluble particulates As an example of the chemical solution contained in the two chambers, the present invention used the following chemical solution composition to measure the status of insoluble particles in the mixed solution after pinching open the tack weld seam and mixing: Composition 1: First solution: Tetracaine hydrochloride, cocaine hydrochloride, propantheline, etc. 0.01% to 0.05% Sodium dihydrogen phosphate 0.01% to 0.09%, Disodium hydrogen phosphate 0.01% to 0.45%, Sodium chloride 0% to 0.9%, Remaining amount: Water, Adjust to pH 3.5-4.5.

[0079] Second solution: Sodium dihydrogen phosphate 0% to 0.09%, Disodium hydrogen phosphate 0% to 0.45%, Sodium chloride 0% to 0.9%, edetate disodium 0% to 0.1%, Adjust to pH 7.0-8.5.

[0080] Composition 2: First solution: Pilocarpine nitrate 1%-2%, warfarin sodium, etc. Sodium citrate hydrate 0.1% to 0.20%, Boric acid 0.5% to 1.0%, Sodium chloride 0% to 0.9%, Remaining amount: Water, Adjust to pH 3-4.

[0081] Second solution: Sodium citrate hydrate 0.5% to 1.0%, Sodium chloride 0% to 0.9%, Benzalkonium chloride 0% to 0.1%, Adjust to pH 7-8.

[0082] The number of insoluble particles in the ophthalmic solution contained in purified water, a single-chamber container manufactured by the tail sealing process, and a dual-chamber container manufactured by the preferred process of the present invention (tack welding was performed using a STD20-1500W ultrasonic welding machine with a LEYH32NZC-50M electric actuator, the welding time was 0.305 seconds, and the torque strength of the electric cylinder was 241 N) was measured using the insoluble particle measurement method specified in the Pharmacopoeia. The measurement results are shown in Table 8 below.

[0083] [Table 8]

[0084] The results showed that the effect of the process of the present invention on the number of insoluble particles in the solution contained in the container was mainly observed in particles larger than 10 μm, but the effect on the content of particles larger than 25 μm in the solution was not statistically significant. Furthermore, even for particles larger than 10 μm, the containers manufactured by the process of the present invention comply with mandatory regulations such as pharmacopoeias.

[0085] Example 5: Heat seal strength measurement method This example describes a method for measuring the heat seal strength of a dual-chamber eye dropper bottle manufactured using the method disclosed herein, with reference to the Chinese National Standard GB / T22638.7-2016 on heat seal strength measurement (which is incorporated herein by reference in its entirety). The method involves removing the outlet and / or tail of a multi-chamber container, forming an opening on one side of the container, selecting two incision positions at the opening, and incising the container wall along a direction parallel to the longitudinal axis of the container to the location where the sealing component is located, so that the container body on that side forms two strips. The container body on the other side is then removed in a manner that leaves only the complete sealing component, finally obtaining a sample for measurement consisting of the complete sealing component and the two strips. The heat seal strength was then measured by clamping the two strips between the upper and lower jigs of a tensioning machine, as shown in Figure 2. During the measurement, one of the jigs was fixed and stationary, while the other was pulled at a constant speed (100 mm / min) until the sealing component was completely peeled off. The maximum tensile force recorded in this process was denoted as Fmax. The selection of the incision positions can be easily determined depending on the structure and direction of the tack weld seam, and specifically, the positions corresponding to the two end points of the long axis of the tack weld seam itself were selected, that is, the connection line between the incision positions and the corresponding end points was selected so as to be parallel to the long axis of the container.

[0086] Taking a dual-chamber container with a 6.5 cm long bottle body (excluding the cap), a 1.2 cm inner diameter, and a 4 mm wide x 15 mm long tack welded seam as an example, the test specimen prepared using the above method included a sealed, complete tack welded seam (4 mm x 15 mm) and two approximately 25 mm long strips (cut from the container body) located on either side of the tack welded seam. The tensile testing machine used in the test was, but was not limited to, a laboratory universal testing machine, model C610M, purchased from Jinan Languang Mechanical & Electrical Technology Co., Ltd.

[0087] The heat seal strength (R) was calculated using the formula R = Fmax / A, where Fmax is the maximum tensile force measured by the above method, and may also be called the maximum peel load, and is expressed in Newtons. A is the length coefficient, which was corrected to A = W / 15 mm. W is the actual length of the tack welded seam present in the test sample (as specifically shown in Figure 2), and is expressed in millimeters. In the example of the sample awaiting measurement, W was 15 mm.

[0088] Example 6: Measurement of heat seal strength Using the method described in Example 2, dual-chamber ophthalmic solution containers disclosed herein were fabricated using two types of medical-grade polyethylene (LDPE) tubing (1810E and 3020D). The resulting containers were approximately 6.5 cm long (excluding the cap), with tack weld seams approximately 4 mm wide and 10 mm long. Using upper and lower limits of the tack weld parameters in the ultrasonic tack welding process to form the sealing components, two samples were fabricated: a test sample group 1 that was perfectly sealed, and a test sample group 2 that could be forcibly opened by hand (verified by an adult male repeatedly performing the pinch-open test described in Table 4).

[0089] Twenty samples were randomly selected from each of the four groups of samples awaiting measurement, and the heat seal strength of the tack-welded seams was measured using the method described in Example 5. The results are shown in Table 9.

[0090] [Table 9]

[0091] As can be seen from Table 9, for the multi-chamber container disclosed herein, when the heat seal strength of the tack-welded seam is within the following numerical range, the sealed portion of the container can completely isolate adjacent chambers and can be pinched open by a user without the aid of external force. The heat seal strength range is 3 Newtons or more, 5 Newtons or more, 7 Newtons or more, 10 Newtons or more, 12 Newtons or more, 14 Newtons or more, or 16 Newtons or more, and 62 Newtons or less, 60 Newtons or less, 58 Newtons or less, 55 Newtons or less, 51 Newtons or less, 45 Newtons or less, 40 Newtons or less, 38 Newtons or less, 34 Newtons or less, or 30 Newtons or less, and preferably 3 to 60 Newtons, 5 to 58 Newtons, 7 to 58 Newtons, 10 to 55 Newtons, 12 to 51 Newtons, or 16 to 38 Newtons.

[0092] Example 7 Five samples were randomly selected from the samples awaiting measurement prepared in Example 6, and the content of insoluble microparticles in the ophthalmic solution after opening the sealed portion was measured using the method described in Example 4. The results are shown in Table 10.

[0093] [Table 10]

[0094] As shown in Table 10, the number of insoluble particles produced after opening the sealing parts of the multi-chamber containers manufactured using the two types of polyethylene tubing was only about 0.7% of the upper limit specified in the Pharmacopoeia in both cases, demonstrating that the containers disclosed in this specification are suitable for use as eye drop containers and that the operation of opening the sealing parts does not cause a significant increase in the number of particles that cause a foreign body sensation. The present invention has been described in detail above. Those skilled in the art will be able to practice the present invention in a relatively wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the present invention and without undue experimentation. While the present invention has been described with specific examples, it should be understood that the present invention can be further improved. In short, in accordance with the principles of the present invention, the present application is intended to cover any changes, uses, or improvements to the present invention, including changes made by ordinary techniques known in the art, that deviate from the scope disclosed herein. Applications of some basic features may be made in accordance with the scope of the following appended claims.

Claims

1. A multi-chamber container for eye drops, the container body (1) comprising two or more drug-containing chambers including at least a first chamber (3) and a second chamber (4), the first chamber (3) communicating with an outlet (5), the remaining chambers connected to the first chamber or other chambers, adjacent chambers separated by a sealing portion (2) and not communicating with each other, characterized in that when an external force is applied to the outer wall of one of the two adjacent chambers, the sealing portion between the two adjacent chambers is irreversibly separated, and when all the sealing portions are separated, each chamber is directly or indirectly connected to the first chamber. Multi-chamber container.

2. The outlet (5) is further provided with a seal cap (6) that can be opened once or repeatedly opened and closed. The multi-chamber container according to claim 1 .

3. The material of the container body is a rigid plastic, and preferably, the thickness of the rigid plastic is 200 to 2000 μm, preferably 350 to 500 μm, more preferably 380 to 400 μm. The multi-chamber container according to any one of claims 1 to 2.

4. The multi-chamber container is characterized in that it is composed of two chambers. The multi-chamber container according to any one of claims 1 to 3.

5. The sealing portion (2) is formed by tack welding the container body using ultrasonic waves with an electric cylinder torque strength of 232-266 Newtons and a welding time of 0.290-0.370 seconds, and optionally, the sealing portion (2) is formed by tack welding the container body using ultrasonic waves with an amplitude of 10%-42% and a welding time of 0.19-0.64 seconds, preferably ultrasonic waves with an amplitude of 36%-39% and a welding time of 0.47-0.49 seconds. The multi-chamber container according to any one of claims 1 to 4.

6. The external force that can irreversibly separate the sealing parts does not exceed the average grip strength of the fingers of a child aged 5 to 7, preferably 17 to 27 Newtons (N). The multi-chamber container according to any one of claims 1 to 5.

7. the heat seal strength of the sealed portion (2) is 3 Newtons or more, 5 Newtons or more, 7 Newtons or more, 10 Newtons or more, 12 Newtons or more, 14 Newtons or more, or 16 Newtons or more, and 62 Newtons or less, 60 Newtons or less, 58 Newtons or less, 55 Newtons or less, 51 Newtons or less, 45 Newtons or less, 40 Newtons or less, 38 Newtons or less, 34 Newtons or less, or 30 Newtons or less, and preferably 3 to 60 Newtons, 5 to 58 Newtons, 7 to 58 Newtons, 10 to 55 Newtons, 12 to 51 Newtons, or 16 to 38 Newtons; The multi-chamber container according to any one of claims 1 to 6.

8. The container further includes a container tail portion (7) formed under sealing conditions in which the cylinder air pressure is 2.0 to 2.5 bar and the welding time is 0.16 to 0.22 seconds; Optionally, the container further includes a container tail portion (7) formed under sealing conditions in which the ultrasonic amplitude is 43% or more and the welding time is 0.65 seconds or more. The multi-chamber container according to any one of claims 1 to 7.

9. The container body is tubular, and preferably, the tubular body has a length of 15 to 180 mm and an inner diameter of 4 to 30 mm. The multi-chamber container according to any one of claims 1 to 8.

10. having a volume of 0.2 mL or more and 20 mL or less; The multi-chamber container according to any one of claims 1 to 9.

11. The sealing portion has an elongated linear structure, or an arched structure with a bend, or an intersecting linear structure with an included angle, and optionally the sealing portion has a uniform and equal width or a variable width, and preferably the width of the sealing portion is 1-20 mm, preferably 2-8 mm, more preferably 4 mm. The multi-chamber container according to any one of claims 1 to 10.

12. An eye drop product comprising a multi-chamber container according to any one of claims 1 to 11, wherein different drugs are filled in the multiple chambers, and at least one of the drugs has a pH value lower than 5.3 or higher than 8.3, and a mixed solution formed by mixing the drugs filled in the multiple chambers has a pH value of 5.3 to 8.3, and the stability of the at least one drug is higher than the stability of the mixed solution formed after mixing the drugs filled in the different chambers. Eye drop products.

13. 13. A method for producing an ophthalmic solution product according to claim 12, said method comprising: Selecting a material suitable for manufacturing into a container body (1) and having a hollow structure with both ends or multiple ends open; forming an outlet (5) at an opening at one end of the hollow structure, the outlet (5) communicating with the first chamber (3), and preferably providing a seal cap (6) at the outlet (5) that can be opened once or repeatedly opened and closed; filling said hollow structure at the opening at the other end with a first predetermined volume of a first medicament when said outlet (5) is in a closed state; tack-welding the hollow structure at a location corresponding to the first predetermined volume to form a separable sealed portion (2), thereby forming a sealed first chamber (3) between the separable sealed portion (2) and the outlet (5), the first agent being contained therein; continuing to fill a second chamber (4) formed between the opening at the other end and the separable sealing portion (2) with a second predetermined volume of a second medicament, different from the first medicament, through the opening at the other end; By this analogy, optionally forming more chambers filled with more different drugs separated from each other by sealing portions; After filling the last one drug into the last one chamber, the last one chamber is sealed by welding to form the container tail portion (7); Including, Thus, the various drugs filled in each chamber can be finally separated from each sealed portion and directly or indirectly mixed with the drug in the first chamber (3), and then discharged from the outlet (5). method.

14. The sealing portions (2) are formed by tack welding using ultrasonic waves with an electric cylinder torque strength of 232-266 Newtons and a welding time of 0.290-0.370 seconds, and the container tail portion (7) is formed by welding and sealing the last chamber using ultrasonic waves with a cylinder pressure of 2.0-2.5 bar and a welding time of 0.16-0.22 seconds, and optionally, the sealing portions (2) are formed by tack welding using ultrasonic waves with an amplitude of 10%-42% and a welding time of 0.19-0.64 seconds, preferably with an amplitude of 36%-39% and a welding time of 0.47-0.49 seconds, and the container tail portion (7) is formed by welding and sealing the last chamber under sealing conditions of an amplitude of 43% or more and a welding time of 0.65 seconds or more.

14. A method for producing the ophthalmic solution product of claim 13.

15. The external force that can irreversibly separate the sealing parts does not exceed the average grip strength of the fingers of a child aged 5 to 7, preferably 17 to 27 Newtons (N). A method for producing the ophthalmic solution product according to any one of claims 13 to 14.

16. the heat seal strength of the sealed portion (2) is 3 Newtons or more, 5 Newtons or more, 7 Newtons or more, 10 Newtons or more, 12 Newtons or more, 14 Newtons or more, or 16 Newtons or more, and 62 Newtons or less, 60 Newtons or less, 58 Newtons or less, 55 Newtons or less, 51 Newtons or less, 45 Newtons or less, 40 Newtons or less, 38 Newtons or less, 34 Newtons or less, or 30 Newtons or less, and preferably 3 to 60 Newtons, 5 to 58 Newtons, 7 to 58 Newtons, 10 to 55 Newtons, 12 to 51 Newtons, or 16 to 38 Newtons; The multi-chamber container according to any one of claims 13 to 15.

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