CN104117137B - Unloaded medicine microneedle array and preparation method thereof in a kind of capsule-type - Google Patents

Abstract

A capsule-type hollow drug-loaded microneedle array and a preparation method thereof belong to the technical field of medical devices. The invention comprises a microneedle base and needle points arrayed on the base; each needle point has a hollow structure inside, and the hollow structure penetrates the base from the inside of the needle point to form a "capsule" structure. The present invention can complete drug administration in a specific area and skin position at one time. Compared with solid microneedles of the same size, the drug loading capacity is greatly increased, and drug activity can be maintained as much as possible. The drug delivery operation efficiency is high, and it is convenient for both doctors and patients. The patient's pain is relieved, and the administration is uniform, and the drug diffusion and onset time are synchronized, thereby effectively improving the effect of transdermal administration. The invention also provides a method for preparing the capsule-type hollow drug-loaded microneedle array.

Description

A capsule-type hollow drug-loaded microneedle array and its preparation method

technical field

The invention relates to a microneedle array for transmitting medicine through the skin, belonging to the technical field of medical devices.

Background technique

The skin is an ideal site for drug delivery. Compared with non-invasive drug delivery methods such as oral administration or topical administration, injection administration has its irreplaceable advantages. Taking intravenous injection as an example, it can directly deliver drugs into the blood, and reach the lesion along with the blood circulation. Compared with oral administration, which uses the digestive tract to absorb drugs, it has a faster speed and higher drug utilization. Not only that, but it can also effectively avoid the burden and unnecessary damage to the digestive system caused by oral medication. The reason why the traditional injection method causes pain is that the existence of the stratum corneum of human skin blocks the transdermal penetration of the drug, and the drug must be effectively absorbed through the barrier through the syringe. However, due to the size limitation of the traditional syringe, it will definitely penetrate the dermis and cause pain nerve excitement, which will bring discomfort to people. However, patients usually do not like this effective and efficient way of subcutaneous injection because of the pain, especially the elderly and young children.

In order to deliver drugs to the human body through the skin, even some macromolecular polypeptides, proteins and DNA, a drug delivery method that can overcome the barrier of the stratum corneum of the skin and relieve the patient's discomfort is needed. Previous studies have concluded that small molecules of drugs or some external energy, such as electric current or ultrasound, can enhance drug penetration.

The use of microneedle technology can achieve painless drug delivery. By controlling the size of the microneedle, it can penetrate the epidermis and cross the stratum corneum without touching the dermis, thereby avoiding contact with nerve fibers and blood. It also avoids bleeding or pain. Microneedles usually come in the form of arrays; a microneedle array can contain tens to hundreds of tiny protrusions, ranging in height from 25 to 2000 microns, attached to a fixed base at the bottom. The manufacturing process of traditional microneedles is usually completed by MEMS technology.

Once the microneedle array is placed on the skin, multiple micropores with a diameter of micron scale can be formed on the skin, which can be used as penetration pathways to transport drug molecules, complexes and particles. Different microneedle types produce different delivery patterns. Common types of microneedles are divided into two categories, solid and hollow. Hollow microneedles are easier to understand and are similar to traditional injection needles; there is a hole in the center of hollow microneedles, which allows drugs to penetrate from the outside to the skin, and can achieve continuous drug delivery. The material is generally metal or silicon. The solid type can be divided into three types according to the different transmission methods: penetrating patch type, coating type and degradable type. The main material of the drug-penetrating microneedle is silicon or stainless steel. Its delivery method is to puncture the skin through the tip. After forming microholes, the microneedle array is removed, and the drug is attached in the form of gel or patch. At the microporous skin, it is transmitted by diffusion or supplemented by other external forces. Coated microneedles are generally made of metal or silicon. The difference between the transmission method and the puncture type is that the drug is coated on the surface of the microneedle in the form of a coating, and then the microneedle is inserted into the skin through the dissolution of the coating. Get the medicine in. The special feature of degradable microneedles is its materials. Sugars, starch chains, degradable acids and ketones and other substances can be used to make degradable microneedles, and the key to making them is to combine drugs with degradable The materials are fused together to make needles with hardness and biocompatibility that meet the specifications. Through the automatic degradation of the microneedles in the body, the drug is released into the body.

From the perspective of current clinical applications, there is no doubt that degradable microneedles are more suitable for clinical applications, mainly because of their good biocompatibility; microneedles made of metal or silicon materials, and their microstructures make them inevitably fall into the skin during use. Thereby causing damage to the human body, which greatly increases the risk of using microneedles of these materials. Degradable microneedles can make up for these problems and are more suitable for clinical applications. However, the current preparation of degradable microneedles depends on the characteristics of the biomaterials formed by the needle body, and it is necessary to fuse the delivered drug with the biomaterial, which may affect the properties of the drug, and the drug loading is low, and it cannot be loaded with live bacteria. Stem cells etc.

Contents of the invention

Aiming at the deficiencies of the prior art, the present invention provides a capsule-type hollow drug-loaded microneedle array and a preparation method thereof, which can maintain the function and performance of the degradable microneedle array, and is simple in structure, safe in use, convenient for self-use, and low in cost. It is cheap, and can increase the drug load, and can be used for subcutaneous delivery of stem cells, live bacteria and other substances.

To achieve the above object, the technical scheme of the present invention is as follows:

A capsule-type hollow drug-loaded microneedle array, the microneedle array includes a base and needle tips arranged on the base; it is characterized in that each needle tip has a hollow structure inside, and the hollow structure penetrates the base from the inside of the needle tip to form a "capsule". ” structure; the substrate of the microneedle array is made of degradable polymer materials.

In the above technical solution, the degradable material is silk fibroin, polyvinyl alcohol, carboxymethyl cellulose, galactose, methyl vinyl ether copolymer, polyvinylpyrrolidone, polyacrylic acid or hyaluronic acid.

Another technical feature of the present invention is: the hollow structure accounts for 1/5-4/5 of the overall height of the needle tip. The shape of the needle tip is pyramid or conical.

The preparation method of a capsule-type hollow drug-loaded microneedle array provided by the present invention is characterized in that the method comprises the following steps:

1) Making microneedle templates: using micro-nano processing technology, laser cutting or mechanical engraving to prepare microneedle templates of silicon materials and metal materials;

2) Making molds: Mix polydimethylsiloxane prepolymer and curing agent in a volume ratio of 8:1 to 12:1, stir well and vacuumize; then, remove the bubbles of liquid polydimethylsiloxane The siloxane is poured onto the microneedle template, and placed in an oven at 70-85°C for 1-2 hours to obtain solid polydimethylsiloxane, which is then torn off from the microneedle template to form a tape Polydimethylsiloxane mold with arrayed pores;

3) The degradable material and deionized water are prepared into a solution according to a mass volume ratio of 1.5-20%, and poured into a polydimethylsiloxane mold;

4) Vacuum for 5-10 minutes, or use a centrifuge to centrifuge at a force of 2500g-3500gg for 30 minutes to 1.5 hours, so that the solution or colloid is fully filled into the pores of polydimethylsiloxane, and then the mold surface layer Remove the solution or colloid, let it stand at room temperature to dry for 10-30 hours, dissolve or dry the colloid to form a film and attach it to the surface of the mold, and separate the cured film from the mold to obtain a degradable capsule-type hollow drug-loaded microparticle. needle array.

The present invention also provides another preparation method of the capsule-type hollow drug-loaded microneedle array, which is characterized in that the method comprises the following steps:

1) Prepare microneedle templates and shaped templates of metal materials by laser cutting or mechanical engraving;

2) Mold making: Mix polydimethylsiloxane prepolymer and curing agent in a volume ratio of 8:1 to 12:1, stir well and vacuumize, and remove the liquid polydimethylsiloxane pour alkane onto the microneedle template, then place it in an oven, and bake it at a temperature of 70°C-85°C for 1-2 hours to obtain solid polydimethylsiloxane, and then solid polydimethylsiloxane The siloxane is torn off from the microneedle template to form a polydimethylsiloxane mold with arrayed pores;

3) The degradable material and deionized water are prepared into a solution or colloid according to a mass volume ratio of 1.5-20%, and poured into a polydimethylsiloxane mold;

4) Vacuum for 5-10 minutes, or use a centrifuge to centrifuge at a force of 2500g-3500gg for 30 minutes to 1.5 hours, so that the solution or colloid is fully filled into the pores of polydimethylsiloxane; The array position in the template is aligned with the array position in the polydimethylsiloxane mold, buckle the shaped template in the solution or colloid on the surface of the polydimethylsiloxane mold, and press it inward; stand at room temperature to dry 10-30 hours; first take out the shaped template, and then remove the cured part of the degradable material from the polydimethylsiloxane mold, and then obtain a degradable capsule-type hollow drug-loaded microneedle array.

Compared with the prior art, the present invention has the following advantages and outstanding effects: ① The microneedle array of the present invention adopts a hollow structure, which has a larger drug loading capacity than degradable solid microneedles, and better maintains drug activity; ②The microneedle array of the present invention is introduced into a stereotyped template to form a complete hollow structure, thus becoming a new method for making hollow microneedles; ③The degradable hollow microneedle array of the present invention encapsulates drugs by means of capsules, and can be used for live bacteria The subcutaneous delivery of biologically active therapeutic drugs such as stem cells and stem cells cannot be realized by the current degradable microneedles; ④ the present invention has the characteristics of simple structure, small size, low cost, convenient use, safety and reliability.

Description of drawings

Fig. 1 is the schematic diagram of the front view of the polydimethylsiloxane (PDMS) mold, microneedle array and stereotyped template of the present invention.

Fig. 2 is a schematic diagram of the structure of a capsule-type hollow drug-loaded microneedle array.

Fig. 3 is a flow chart of manufacturing a capsule-type hollow drug-loaded microneedle array by a dual-mode method.

Fig. 4 is a front view schematic diagram of a PDMS mold and a microneedle template of an embodiment of a capsule-type hollow drug-loaded microneedle array.

Fig. 5 is a schematic diagram of a microneedle template structure of an embodiment of a capsule-type hollow drug-loaded microneedle array.

Fig. 6 is a schematic diagram of a shaped template structure of an embodiment of a capsule-type hollow drug-loaded microneedle array.

In the figure: 1-needle tip; 2-base; 3-hollow structure; 4-polydimethylsiloxane mold; 5-setting template; 6-card slot; 7-microneedle template.

detailed description

The principle, structure and implementation of the present invention will be described in detail below with reference to the accompanying drawings.

The present invention provides a capsule-type hollow drug-loaded microneedle array, which includes a base 2 and needle tips 1 arrayed on the base. Each needle tip has a hollow structure 3 inside, and the hollow structure penetrates the base 2 from the inside of the needle tip 1 to form a " Capsule" structure. The substrate of the microneedle array is made of degradable polymer materials, such as silk fibroin, polyvinyl alcohol, carboxymethyl cellulose, galactose, methyl vinyl ether copolymer, polyvinylpyrrolidone, Polyacrylic acid or hyaluronic acid.

The hollow structure of the present invention generally accounts for 1/5-4/5 of the overall height of the needle tip; the shape of the needle tip is pyramidal or conical (as shown in Figure 2).

The preparation method of the capsule-type hollow drug-loaded microneedle array provided by the present invention specifically includes the following steps:

1) Making microneedle templates: using micro-nano processing technology, laser cutting or mechanical engraving to prepare microneedle templates of silicon materials and metal materials;

2) Making molds: Mix polydimethylsiloxane prepolymer and curing agent in a volume ratio of 8:1 to 12:1, stir well and vacuumize; then, remove the bubbles of liquid polydimethylsiloxane The siloxane is poured onto the microneedle template, and placed in an oven at 70-85°C for 1-2 hours to obtain solid polydimethylsiloxane, which is then torn off from the microneedle template to form a tape Polydimethylsiloxane mold with arrayed pores;

3) The degradable material and deionized water are prepared into a solution according to a mass volume ratio of 1.5-20%, and poured into a polydimethylsiloxane mold;

4) Vacuum for 5-10 minutes, or use a centrifuge to centrifuge at a force of 2500g-3500gg for 30 minutes to 1.5 hours, so that the solution or colloid is fully filled into the pores of polydimethylsiloxane, and then the mold surface layer Remove the solution or colloid, let it stand at room temperature to dry for 10-30 hours, dissolve or dry the colloid to form a film and attach it to the surface of the mold, and separate the cured film from the mold to obtain a degradable capsule-type hollow drug-loaded microparticle. needle array.

Another method for preparing a capsule-type hollow drug-loaded microneedle array provided by the present invention comprises the following steps:

1) Prepare microneedle templates and shaped templates of metal materials by laser cutting or mechanical engraving;

2) Mold making: Mix polydimethylsiloxane prepolymer and curing agent in a volume ratio of 8:1 to 12:1, stir well and vacuumize, and remove the liquid polydimethylsiloxane pour alkane onto the microneedle template, then place it in an oven, and bake it at a temperature of 70°C-85°C for 1-2 hours to obtain solid polydimethylsiloxane, and then solid polydimethylsiloxane The siloxane is torn off from the microneedle template to form a polydimethylsiloxane mold with arrayed pores;

3) The degradable material and deionized water are prepared into a solution or colloid according to a mass volume ratio of 1.5-20%, and poured into a polydimethylsiloxane mold;

4) Vacuum for 5-10 minutes, or use a centrifuge to centrifuge at a force of 2500g-3500gg for 30 minutes to 1.5 hours, so that the solution or colloid is fully filled into the pores of polydimethylsiloxane; The array position in the template is aligned with the array position in the polydimethylsiloxane mold, buckle the shaped template in the solution or colloid on the surface of the polydimethylsiloxane mold, and press it inward; stand at room temperature to dry 10-30 hours; first take out the shaped template, and then remove the cured part of the degradable material from the polydimethylsiloxane mold, and then obtain a degradable capsule-type hollow drug-loaded microneedle array.

The drawings of the present invention adopt a microneedle array with a 3*3 structure, and the structure of the microneedle array is closely related to the manufacturing method of the microneedle array. Generally speaking, the shape of the microneedle can be appropriately set so that it can easily penetrate into the skin, dissolve in the body without causing pain or bleeding, and a quadrangular pyramid shape is preferred. When the microneedle without ribs penetrates the skin, due to the elasticity of the skin, it will generate resistance from all directions, and finally overcome the resistance and enter the skin, causing tearing damage to the skin. The pressure will generate shear force on the skin, and the skin will be cut along the edge direction, reducing resistance and avoiding severe pulling on the skin, thereby reducing wounds.

Fig. 1 is a schematic diagram of the front view of the polydimethylsiloxane mold of the capsule-type hollow drug-loaded microneedle array, the microneedle array, and the stereotyped template. The three modules can be perfectly combined according to the concave-convex structure of the surface. Wherein, the two sides of the microneedle template 7 and the shaped template 5 have slots 6, which can be used to determine the thickness of the substrate, and at the same time make the positioning of the microneedles accurate during the manufacturing process.

Fig. 3 is a flow chart of making a capsule-type hollow drug-loaded microneedle array by a dual-mode method. Use silicon or metal materials and other non-degradable materials to make microneedle templates and stereotyped templates, use microneedle templates to make PDMS molds, and then make the selected materials for making degradable microneedles into solutions or colloids, and pour them Put it into the PDMS mold, after a period of centrifugation, buckle the shaping template, and get the microneedle array after drying.

Fig. 4 is a front view (section) schematic diagram of the PDMS mold and microneedle template of the capsule-type hollow drug-loaded microneedle array. Ensure that the liquid PDMS can completely wrap the microneedle template.

Fig. 5 is a schematic diagram of the microneedle template structure of the capsule-type hollow drug-loaded microneedle array. It is made of metal materials and other non-degradable materials by laser cutting process.

Fig. 6 is a schematic diagram of the shaped template structure of the capsule-type hollow drug-loaded microneedle array. It is made of metal materials and other non-degradable materials by laser cutting process.

Comparing the degradable hollow microneedle of the present invention with the previous hollow microneedle, the previous hollow microneedle is generally made of non-degradable material, and there is a hole in the center of the needle tip, which can allow the drug to penetrate from the outside to the skin, which can realize continuous drug administration The process can be used continuously; while the hollow microneedles are made of degradable materials and can be used at one time, which is equivalent to a drug capsule that enters the human body through the skin.

Due to the large internal space of the microneedles, different drugs can be stored, as well as drugs with larger particles, and can also be used for subcutaneous delivery of stem cells and live bacterial cells.

The drug release method of the degradable hollow microneedle array in the present invention can be mixed with the previous degradable material and the drug. After the microneedle array is pierced into the skin, the degradable needle tip will be released within a certain period of time after encountering the body fluid. Dissolving to release the drug; it is also possible to store the drug in the hollow structure of the microneedle array. Since the size of the microneedle is on the micron scale, the drug solution can be adsorbed in the hollow structure by capillary action, and at the same time, the sealing film is used to seal the microneedle. After the needle array is pierced into the skin, the degradable needle tip will dissolve within a certain period of time when it encounters body fluid, thereby releasing the drug stored in the hollow structure; the two methods can also be combined. These delivery and release designs can be designed according to the application requirements of different drugs to meet the needs of different clinical medications.

Example 1:

(1) The needle template of stainless steel material was prepared by laser cutting method.

(2) Make a PDMS mold using a microneedle template. Mix the PDMS prepolymer and the curing agent at a volume ratio of 10:1, stir well and vacuumize; then, pour the liquid polydimethylsiloxane that removes the bubbles onto the microneedle template, and place it in an oven at 80°C Medium-baked for 1.5 hours to obtain solid polydimethylsiloxane, which was then torn off from the microneedle template to form a polydimethylsiloxane mold with arrayed micropores. ;

(3) pouring a silk fibroin solution with a mass volume ratio of 8% into a polydimethylsiloxane mould;

(4) Vacuum for 5 minutes, remove the silk fibroin solution on the surface of the mold, leave it to dry at room temperature for 20 hours, dry the silk fibroin solution to form a film and attach it to the surface of the mold, separate the cured film from the mold, That is, the silk fibroin hollow microneedle array is obtained.

Example 2:

(1) The stainless steel needle template and shaping template were prepared by laser cutting method.

(2) Make a PDMS mold using a microneedle template. Mix the PDMS prepolymer and the curing agent at a volume ratio of 10:1, stir well and vacuumize; then, pour the liquid polydimethylsiloxane that removes the bubbles onto the microneedle template, and place it in an oven at 80°C Medium-baked for 1.5 hours to obtain solid PDMS oxane, which was then torn off from the microneedle template to form a PDMS mold with arrayed micropores. ;

(3) pouring a polyethylene solution with a mass volume ratio of 15% into a PDMS mould;

(4) Vacuumize for 5 minutes. Align the array position in the shaped template with the array position in the PDMS mold through the card slot, buckle the shaped template on the polyethylene solution on the surface of the PDMS mold, and press it inward. Leave to dry at room temperature for an hour. First take out the shaping template, and then remove the polyethylene cured part from the PDMS mold to become a hollow microneedle array of polyethylene material.

In the present invention, the microneedle array can deliver various transdermally injectable drugs, macromolecular drugs, DNA, vaccines, cells, bacteria, special material drugs, etc.

Claims (5)

1. unloaded medicine microneedle array in a kind of capsule-type, the microneedle array contains substrate (2) and array is arranged in substrate Needle point (1)；It is characterized in that：There is hollow structure (3), hollow structure (3) passes through inside needle point (1) inside each needle point (1) Substrate (2) is worn, forms " capsule " formula structure；The needle point (1) and the hollow structure (3) are in rectangular pyramid；Microneedle array Base material use degradable high polymer material, the size of the micropin of the microneedle array is made in micron order, drug solution by capillary With absorption in the hollow structure, while carry out sealing the hollow structure using diaphragm seal；Described degradable macromolecule Material is using fibroin albumen, polyvinyl alcohol, carboxymethyl cellulose, galactolipin, methyl vinyl ether copolymer, polyvinylpyrrolidine Ketone, polyacrylic acid or hyaluronic acid.

2. unloaded medicine microneedle array in a kind of capsule-type as claimed in claim 1, it is characterised in that：Described hollow structure accounts for The 1/5~4/5 of needle point whole height.

3. unloaded medicine microneedle array in a kind of capsule-type as claimed in claim 1, it is characterised in that：The shape of described needle point For pyramid or cone.

A kind of 4. preparation method of unloaded medicine microneedle array in capsule-type as claimed in claim 1, it is characterised in that this method bag Include following steps：

1) microneedles template is made：Silicon materials, gold are prepared using the method for micro-nano processing technology, laser cutting or mechanical engraving Belong to the microneedles template of material；

2) mould is made：It is 8 by volume by polydimethylsiloxane prepolymer thing and curing agent:1 to 12:1 is mixed, fully Stir and vacuumize；Then, the liquid dimethyl silicone polymer for removing bubble is poured on microneedles template, as 70- In 85 DEG C of baking oven, 1-2 hours, that is, the dimethyl silicone polymer of solid-state is obtained, then it tears from microneedles template, formed The dimethyl silicone polymer mould of micropore with array-like；

3) again by degradation material and deionized water according to 1.5-20% mass volume ratio wiring solution-forming, it is poured into poly dimethyl In silicone mold；

4) 5-10 minutes are vacuumized, or are centrifuged 30 minutes to 1.5 hours with 2500g-3500g dynamics using centrifuge, are made Obtain solution or colloid be sufficiently filled in the hole of dimethyl silicone polymer, then remove the solution on mould top layer or colloid, Normal temperature, which is stood, to be dried 10-30 hours, and solution or colloid drying and forming-film are attached to die surface, will solidify obtained film from mould Separate, that is, obtain unloaded medicine microneedle array in degradable capsule-type.

A kind of 5. preparation method of unloaded medicine microneedle array in capsule-type as claimed in claim 1, it is characterised in that this method bag Include following steps：

1) microneedles template and typified form of metal material are prepared using the method for laser cutting or mechanical engraving；

2) mould is made：It is 8 by volume by polydimethylsiloxane prepolymer thing and curing agent:1 to 12:1 is mixed, fully Stir and vacuumize, the liquid dimethyl silicone polymer for removing bubble is poured on microneedles template, is subsequently placed in baking oven In, 1-2 hours are toasted at a temperature of 70 DEG C -85 DEG C, that is, obtain the dimethyl silicone polymer of solid-state, then the poly- diformazan by solid-state Radical siloxane is torn from microneedles template, forms the dimethyl silicone polymer mould with array-like micropore；

3) degradation material and deionized water are poured into poly- two according to 1.5-20% mass volume ratio wiring solution-forming or colloid In methylsiloxane mould；

4) 5-10 minutes are vacuumized, or are centrifuged 30 minutes to 1.5 hours with 2500g-3500g dynamics using centrifuge, are made Obtain solution or colloid is sufficiently filled in the hole of dimethyl silicone polymer；By neck by the array position in typified form with In dimethyl silicone polymer mould array position align, by typified form be buckled in dimethyl silicone polymer die surface solution or In person's colloid, and inwardly compress；Normal temperature, which is stood, dries 10-30 hours；First take out typified form, then from dimethyl silicone polymer mould The part of degradation material solidification is removed on tool, that is, obtains unloaded medicine microneedle array in degradable capsule-type.