Oral solid controlled release formulation based on microdroplet ejection and method of preparation thereof

Abstract

The application belongs to the field of drug design, and discloses a preparation method of oral solid controlled-release preparation based on micro-droplet spraying, comprising the following steps: S1, separating and designing the distribution of active pharmaceutical ingredients and pharmaceutical excipients in the preparation; S2, recombining the ingredient information after the separation and design; S3, converting the ingredient distribution information after the combination into a slice recognizable by a 3D printing device; S4, printing by using a double-channel micro-droplet spraying 3D printer; and S5, using a powder material to receive the ingredients sprayed by the printer, so as to bond and form a solid preparation. The concentration gradient function defined by the application defines the concentration distribution method of the active pharmaceutical ingredients in the preparation, and solves the problem that the controlled-release preparation cannot achieve ideal controlled-release effect in principle; the 3D printing of the oral solid controlled-release preparation by using the double-channel micro-droplet spraying principle can change the existing preparation process mode, and can prepare the oral solid controlled-release preparation meeting the functional design requirements.

Description

Technical Field

[0001] This invention belongs to the field of drug design and manufacturing, specifically relating to an oral solid controlled-release formulation based on microdroplet injection and its preparation method. Background Technology

[0002] Drugs are substances that can be used to treat, prevent, or diagnose diseases in humans and animals, and that affect the physiological functions of the body. Drugs have a significant impact on human life, health, and public health security, and are also necessities for everyone. There are many types of drugs, among which oral solid controlled-release formulations (OSCs) release drugs slowly and at a constant rate in a specified release medium. Compared to corresponding conventional formulations, the dosing frequency is reduced by half or slightly, blood drug concentrations are more stable than sustained-release formulations, and patient compliance is significantly improved. OSCs have attracted much attention due to their convenience, slow release, low toxicity, good efficacy, and timed and targeted drug release. They are suitable for patients requiring long-term medication and reduce the frequency of medication for the elderly, children, and patients with difficulty swallowing solids. Therefore, OSCs have significant application value in the treatment of human diseases.

[0003] To effectively improve the drug release effect of oral solid controlled-release formulations, researchers have sought ways to achieve the ideal controlled-release effect by changing the shape of the formulation and the composition of pharmaceutical excipients. However, no matter how the formulation structure and the composition of pharmaceutical excipients are changed, the uniform distribution of drug components in the formulation will ultimately prevent the amount of drug dissolved per unit time from maintaining a stable level, thus failing to achieve the ideal controlled-release effect. Summary of the Invention

[0004] The purpose of this invention is to provide an oral solid controlled-release formulation based on microdroplet injection and its preparation method, thereby solving the technical problem in the prior art where the uniform distribution of active pharmaceutical ingredients within the formulation leads to unsatisfactory controlled-release effects.

[0005] This invention is achieved through the following technical solution:

[0006] A method for preparing an oral solid controlled-release formulation based on microdroplet injection includes the following steps:

[0007] S1. Design the separation of active pharmaceutical ingredients and pharmaceutical excipients in the formulation;

[0008] The separation design specifically involves using a concentration gradient function to define the concentration of the active pharmaceutical ingredient at different locations within the formulation.

[0009] S2. Recombine the component information after separation design to obtain the combined component distribution information;

[0010] S3. The combined component distribution information is converted into slices that can be recognized by the microdroplet jet 3D printing equipment;

[0011] S4. Print using a dual-channel microdroplet jet 3D printer;

[0012] S5. Pharmaceutical excipient powder material is used to receive the components sprayed by the printer, thereby binding them to form an oral solid controlled-release formulation.

[0013] Furthermore, in S1, the concentration gradient function is specifically:

[0014] Assuming that the entire area of ​​a sphere with radius R and center of the formulation is filled with active pharmaceutical ingredients, and the concentration of active pharmaceutical ingredients at the center of the sphere is set to 1, a concentration gradient function is constructed with the distance from any point in the formulation space to the center of the formulation as the independent variable and the concentration of active pharmaceutical ingredients in the formulation as the dependent variable.

[0015] The spray concentration of the binder is complementary to the spray concentration of the active pharmaceutical ingredient, and the total amount of the two remains constant.

[0016] Furthermore, the expression for the concentration gradient function is:

[0017]

[0018] In the formula, ρ is the distance from any point in the formulation to the center of the formulation, a is a correction constant, R is the average radius of the formulation, and Δρ is the thickness of the high-concentration drug layer on the outer skeleton.

[0019] Furthermore, using a cylinder as the three-dimensional model of the formulation, the expression for the concentration gradient function is:

[0020]

[0021] x and y are the coordinates of the formulation in the three-dimensional model.

[0022] Furthermore, in S2, the recombination of the component information after separation design is specifically as follows:

[0023] The distribution information of active pharmaceutical ingredients in the same spatial location in the formulation is combined with the distribution information of the binder.

[0024] Furthermore, S3 specifically involves defining the recombined information by assigning different colors to different components, and using color to define material distribution for slice output.

[0025] Furthermore, S4 specifically involves: using a dual-channel microdroplet jet 3D printer for printing preparation, with one channel jetting the active pharmaceutical ingredient and the other channel jetting the adhesive ingredient, and using pharmaceutical excipient powder as a carrier to support the dual-channel powder containing the two ingredients.

[0026] This invention discloses an oral solid controlled-release formulation prepared by the aforementioned method.

[0027] Compared with the prior art, the present invention has the following beneficial technical effects:

[0028] This invention discloses an oral solid controlled-release formulation based on microdroplet jetting and its preparation method. The gradient function definition method proposed in this invention, which defines the concentration distribution of the active pharmaceutical ingredient in the formulation, solves the problem that controlled-release formulations cannot achieve the ideal controlled-release effect in principle, and the design process is more scientific and reasonable. The oral solid controlled-release formulation prepared by 3D printing using the dual-channel microdroplet jetting principle proposed in this invention can change the existing preparation process, can prepare oral solid controlled-release formulations that meet the function design requirements, and shorten the equipment development cycle. Attached Figure Description

[0029] Figure 1 This is the function graph corresponding to the gradient function in this embodiment of the invention;

[0030] Figure 2 This diagram illustrates how the coordinate system of the formulation's three-dimensional model was established in an embodiment of the present invention.

[0031] Figure 3 This is the process of combining the distribution information of the two components and the final single-layer slice image in an embodiment of the present invention;

[0032] Figure 4 These are cross-sectional images of the formulation at equal intervals in the height direction in the embodiments of the present invention;

[0033] Figure 5 This is a three-dimensional model diagram showing the distribution of each component in the formulation in an embodiment of the present invention;

[0034] Figure 6 This is a schematic diagram of the printing device in an embodiment of the invention.

[0035] Among them, 1 is Material 1 and 2 is Material 2. Detailed Implementation

[0036] To make the objectives, technical solutions, and advantages of the present invention clearer, the following detailed description is provided in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention; that is, the described embodiments are only a part of the embodiments of the present invention, and not all of them.

[0037] The components described and illustrated in the accompanying drawings and embodiments of this invention can be arranged and designed in various different configurations. Therefore, the detailed description of the embodiments of the invention provided in the following drawings is not intended to limit the scope of the claimed invention, but merely to illustrate one selected embodiment of the invention. All other embodiments obtained by those skilled in the art based on the accompanying drawings and embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0038] This invention discloses a method for preparing an oral solid controlled-release formulation based on microdroplet injection, comprising the following steps:

[0039] S1. Design the separation of active pharmaceutical ingredients and pharmaceutical excipients in the formulation;

[0040] S2. Recombine the component information after separation design;

[0041] S3. The combined component distribution information is converted into slices that can be recognized by the microdroplet jet 3D printing equipment;

[0042] S4. Print using a dual-channel microdroplet jet 3D printer;

[0043] S5. The powder material is used to receive the components sprayed by the printer, thereby binding them to form a solid preparation.

[0044] The specific implementation process of the separation design in step S1 is as follows:

[0045] Design the concentration gradient function of the active pharmaceutical ingredient in the formulation: Assume that the entire sphere within the radius R of the center of the formulation contains the active pharmaceutical ingredient, and set the concentration of the active pharmaceutical ingredient at this location to be 1. Construct a distribution gradient function of the active pharmaceutical ingredient with the distance from any point in the formulation space to the center of the formulation as the independent variable and the concentration of the active pharmaceutical ingredient in the formulation as the dependent variable. The specific expression can be freely set by the designer.

[0046] The spray concentration of the adhesive must be complementary to the spray concentration of the active pharmaceutical ingredient, and the total amount of the two should remain constant.

[0047] The concentration of active pharmaceutical ingredient and the distribution concentration of binder at any spatial location within the formulation can be controlled by using function definition. In the design process, only the gradient function of the active pharmaceutical ingredient needs to be changed to realize the drug distribution design process of any form of controlled-release formulation.

[0048] The specific implementation process of recombinizing the component information in step S2 is as follows:

[0049] By using color definition, different color information is used to replace the distribution information of different components, and the drug concentration information and binder concentration information at the same point in the formulation space are combined.

[0050] In step S3, the combined information obtained in step S2 is output, its format is converted, and finally a slice that can be recognized by the printer is output.

[0051] This invention addresses the problem in existing technologies where the uniform distribution of active pharmaceutical ingredients in formulations prevents the achievement of ideal controlled-release effects. It proposes a method for designing and preparing oral solid controlled-release formulations based on the microdroplet jetting principle, utilizing a concentration gradient function design. By designing a concentration gradient function, the distribution information of the two components is reconstructed, ultimately yielding 3D-printed slices that meet the printer's input requirements. This printing process enables control over the distribution of the active pharmaceutical ingredient within the formulation space.

[0052] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0053] Specifically, embodiments of the present invention provide a custom concentration gradient function, the graph of which is shown below. Figure 1 As shown:

[0054]

[0055] In the formula, ρ is the distance from any point in the formulation to the center of the formulation, a is a correction constant, R is the average radius of the formulation, and Δρ is the thickness of the high-concentration drug layer on the outer skeleton.

[0056] Next, a three-dimensional Cartesian coordinate system will be established at the center of the formulation, and the coordinates of any point within the formulation's internal space will be substituted into the gradient function to obtain the specific gradient function. In this example, a cylinder is used as the three-dimensional model of the formulation. Figure 2 This describes the method for establishing the coordinate system within the three-dimensional model of the formulation. The gradient function, after specification, is as follows:

[0057]

[0058] In the formula, x and y are the coordinates of the formulation in the three-dimensional model.

[0059] In this example, the correction constant a is set to 0, the average radius R of the formulation is set to 5, and the formulation height is set to 5.

[0060] According to formula (2), combined with the geometric dimensions of the formulation designed by the designer, the corresponding output accuracy can be obtained, and the distribution information of the active drug component in the formulation space can be obtained. By continuing to use this method, the distribution information of the binder in the formulation can be defined.

[0061] The two types of distribution information are combined, and then the distribution information of active pharmaceutical ingredients and adhesives are output using two different color channels. In this example, yellow represents active pharmaceutical ingredients and black represents adhesives. The two types of information are combined at the same location, and finally, slices that meet the printer input format requirements are output. Figure 3 This describes the process of combining the distribution information of the two components and the final single-layer slice image. Figure 4 This is a cross-section of the formulation at equal intervals along the height direction.

[0062] Figure 5 This is a three-dimensional model diagram of the distribution of the various components of the formulation. White represents the active pharmaceutical ingredient, and black represents the binder component. Figure 5 As can be seen, the concentration of the active pharmaceutical ingredient gradually decreases from the center of the formulation to the surrounding areas, forming a drug concentration gradient.

[0063] Then use such as Figure 6 The dual-channel microdroplet jetting 3D printer shown is used for printing and preparation. Material 1 is the active pharmaceutical ingredient, and Material 2 is the binder. Powdered pharmaceutical excipients are used as carrier materials to receive the jetted active pharmaceutical ingredient and binder component. After layer-by-layer deposition, the preparation entity is finally formed.

[0064] To achieve the desired controlled-release effect, the distribution of the active pharmaceutical ingredient within the formulation must be altered. By changing the distribution of the active pharmaceutical ingredient within the formulation, the release amount of the active pharmaceutical ingredient can be controlled, ensuring a constant release amount per unit time and achieving the desired controlled-release effect.

[0065] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the specific implementation of the present invention. Any modifications or equivalent substitutions that do not depart from the spirit and scope of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. A process for the preparation of a microdroplet ejection based oral solid controlled release formulation, characterized by, The method comprises the following steps: S1, separating the distribution of active pharmaceutical ingredients and pharmaceutical excipients in the preparation; The separation design is specifically defined as follows: the concentration of active pharmaceutical ingredients at different positions in the preparation is defined by using a concentration gradient function; S2, recombining the component information after separation design to obtain combined component distribution information; S3, converting the combined component distribution information into slices recognizable by a micro-droplet jet 3D printing device; S4, printing using a double-channel micro-droplet jet 3D printer; S5, using pharmaceutical excipient powder material to receive the components sprayed by the printer to form an oral solid controlled-release preparation by adhesion; In S1, the concentration gradient function is specifically defined as follows: Assuming that the center of the preparation is the center of a sphere with a radius R, and the concentration of active pharmaceutical ingredients at the center is 1, a concentration gradient function is constructed with the distance from any point in the preparation space to the center of the preparation as the independent variable, and the concentration of active pharmaceutical ingredients in the preparation as the dependent variable; The printing concentration of the binder is complementary to the printing concentration of the active pharmaceutical ingredients, and the total amount of the two is kept constant; The expression of the concentration gradient function is: ； wherein is the distance from any point in the formulation to the center of the formulation, is the correction constant, is the average radius of the formulation, is the thickness of the high drug concentration layer of the outer layer of the matrix.

2. A process for the preparation of a microdroplet ejection based oral solid controlled release formulation according to claim 1, characterized in that, A cylinder is used as the three-dimensional model of the preparation, and the expression of the concentration gradient function is: ； x, y are the coordinates of the preparation in the three-dimensional model.

3. A process for the preparation of a microdroplet ejection based oral solid controlled release formulation as claimed in claim 1, wherein, In S2, the recombination of the component information after separation design is specifically defined as follows: The active pharmaceutical ingredient distribution information and the binder distribution information at the same spatial position in the preparation are combined.

4. A process for the preparation of a microdroplet ejection based oral solid controlled release formulation as claimed in claim 1, wherein, S3 is specifically defined as follows: the recombined information is defined by assigning different colors to different components, and the slice output is performed by using the color definition material distribution method.

5. A process for the preparation of a microdroplet ejection based oral solid controlled release formulation as claimed in claim 1, wherein, S4 is specifically defined as follows: printing is performed using a double-channel micro-droplet jet 3D printer, one channel sprays active pharmaceutical ingredients, the other channel sprays binder components, and pharmaceutical excipient powder is used as a carrier to receive the double-channel powder of the two components.

6. An oral solid controlled-release preparation based on micro-droplet jet prepared by the preparation method of any one of claims 1-5.

Images