CN214158121U - Long-acting intelligent implantable drug carrying device - Google Patents
Long-acting intelligent implantable drug carrying device Download PDFInfo
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- CN214158121U CN214158121U CN202022364596.7U CN202022364596U CN214158121U CN 214158121 U CN214158121 U CN 214158121U CN 202022364596 U CN202022364596 U CN 202022364596U CN 214158121 U CN214158121 U CN 214158121U
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Abstract
The utility model belongs to the field of pharmaceutics, concretely relates to long-term intelligent implanted medicine carrying device. A long-acting intelligent implantable drug delivery device comprising: the inner part of the outer sleeve is divided into an A cavity and a B cavity by an isolating membrane; the cavity A is an organic solvent chamber and is used for storing organic solvent; the cavity B is used for storing a boosting agent; the inner medicine carrying tube can be nested inside the cavity B of the outer sleeve; the inner drug-carrying tube comprises a columnar adsorbing material which is used for adsorbing active drug components; the end part of the inner medicine carrying tube facing to the side of the cavity B is also provided with a semipermeable membrane medicine releasing hole, and a semipermeable membrane is arranged in the semipermeable membrane medicine releasing hole and is used for releasing the active medicine component outwards. The device can accurately control the release rate, release period, intermittent release, application period and the like of the device.
Description
Technical Field
The utility model belongs to the field of pharmaceutics, in particular to an implanted long-acting controlled release drug delivery device.
Background
Growth hormone deficiency is a growth and development disorder in children caused by insufficient growth hormone secreted by anterior pituitary, and has the main symptoms of hypoevolutism and short stature, which can be divided into three different types of primary, acquired and temporary. Some children are clinically diagnosed with dwarfism caused by growth hormone deficiency, and exogenous growth hormone supplementation is the only safe and effective treatment means. Growth hormone needs to be injected once a day, and through continuous innovation and research, a water injection preparation which only needs to be injected once a week is a long-acting product on the market, so that the compliance of children with the medicine is effectively improved compared with the pain caused by daily injection. However, the disadvantage of frequent injections is obvious, and not only long-term traumatic stimulation is caused to the skin, but also the psychological fear and psychological trauma brought to the physical and mental development stage of children by frequent and long-term injections are more important.
The prior art has proposed a technology for preparing macromolecule long-acting slow-release microspheres, and the current research situation is as follows: in 1995, the first recombinant human growth hormone long-acting microsphere preparation in the world was developed by the American gene Take, and the cost is very high because the macromolecular biological preparation is very sensitive to a solvent required for preparing the microsphere, mechanical shearing force in a stirring process and the like, and the activity of a protein drug can be maintained in a low-temperature environment of liquid nitrogen as a whole. This once-a-month injected dosage form, due to the limitations of technology at the time: the manufacturing cost is too high, and the problem that the material is slowly degraded to form an acidic environment after subcutaneous injection to cause irritation is finally caused, so that the market is finally released.
Therefore, the problem of frequent injection of common preparations still cannot be thoroughly solved, a long-acting injection type is still urgently needed in clinic at present, and due to the high instability of protein medicines, the harsh requirements on the manufacturing process and the like, a mild preparation process with stable manufacturing process and no obvious damage to the activity of protein is urgently needed, and the device is developed based on the requirement.
SUMMERY OF THE UTILITY MODEL
The existing recombinant human growth hormone dosage form generally has the defects of low child acceptance, great family burden and poor cost performance, so that the patent provides an implanted long-acting controlled-release drug delivery device to make up for the clinical blank. Meanwhile, the device can be used for developing and utilizing other medicines such as chemical medicines, plant medicines, biological medicines, gene medicines, cell medicines and the like.
A long-acting smart implantable drug delivery device comprising:
the inner part of the outer sleeve is divided into an A cavity and a B cavity by an isolating membrane; the cavity A is used for storing boosting agent; the cavity B is an organic solvent chamber for storing organic solvent;
the inner medicine carrying tube can be nested inside the cavity B of the outer sleeve; the inner drug-carrying tube comprises a columnar adsorbing material which is used for adsorbing active drug components;
the end part of the inner medicine carrying tube, which is back to the side of the cavity B, is also provided with a semipermeable membrane medicine releasing hole, and a semipermeable membrane is arranged in the semipermeable membrane medicine releasing hole and is used for releasing active medicine components outwards.
In one embodiment, the outer surface of the cavity A is also provided with a penetration hole.
In one embodiment, further comprising: the inner sleeve and the outer sleeve are nested and arranged at the end part of one side of the cavity B of the outer sleeve and used for fixing the outer sleeve and the inner drug-carrying tube.
In one embodiment, further comprising: and the hardening framework is positioned inside the adsorbing material and is used for puncturing the isolating membrane 9.
In one embodiment, further comprising: and the locking device is used for fixing the outer sleeve and the inner medicine carrying pipe and preventing the inner medicine carrying pipe from puncturing the isolating membrane.
In one embodiment, the locking device is removably connected to the outer cannula and the inner drug-carrying tube.
In one embodiment of the method of the present invention,the surface porosity of the adsorbing material can be 70-95%, the pore size can be 0.5-200um, and the pore density can be 100-2。
In one embodiment, the outer surface of the adsorbent material is coated with a PLGA polylactic acid film.
In one embodiment, a spiral medicine release channel is further arranged inside the adsorbing material.
In one embodiment, the spiral drug release channel is formed by channels which are arranged around the cylinder core for 2-10 weeks, the number of the channels is 2-20, and the diameter of the cylinder section is 1-10 mm.
In one embodiment, the outer sleeve and the inner drug-carrying tube are made of PLGA, biodegradable magnesium alloy material, PCL and PCL/PDLLA copolymer, SAIB copolymer and the like, and the outer sleeve and the inner drug-carrying tube are made of single component or two or more components.
In one embodiment, the material of the semipermeable membrane may be cellulose acetate, polytetrafluoroethylene, or the like.
In one embodiment, the organic solvent is selected from one or more of hydrogenated saturated soybean phospholipid, ethanol, methyl pyrrolidone NMP and propylene glycol.
In one embodiment, the boosting agent is selected from the group consisting of mannitol, sodium chloride, PEO, and like water-swellable materials.
The manufacturing method of the long-acting intelligent implantable drug carrying device comprises the following steps:
and 4, connecting the outer sleeve and the inner medicine carrying pipe, placing the outer sleeve and the inner medicine carrying pipe, and adding a locking device.
Has the advantages that:
the preparation and the use of the traditional long-acting microsphere, the solid nanoparticle and the drug-loaded long-acting implant device have the following defects:
(1) the preparation process is complex, the biological medicine is difficult to bear, and the 3-dimensional structure of the biological medicine is easily changed by heat, stirring, a surfactant, oil-water interfacial tension and water-vapor interfacial tension in the process so as to cause the loss of the medicine activity to different degrees
(2) The implant rod (such as a contraceptive rod and the like) made of the non-degradable polymer material needs to be taken out by operation after the drug is released, so that secondary damage to human tissues is caused.
(3) Has a certain burst release effect, has a high proportion of release in the initial stage of implantation, has large fluctuation of later release, causes large fluctuation of blood concentration in a patient body, and has potential hazard.
The advantages of the novel implantable long-acting controlled-release drug delivery device are as follows:
(1) the macromolecular protein drug (1 year of therapeutic agent dosage) is added into the drug-loading tube device in the reservoir for the first time, and the stability is greatly improved because the drug is stored in a solid powder form. The device can accurately control the release rate, the release period, the intermittent release, the pesticide application period and the like of the device by combining semipermeable membranes, biological material erosion degradation, micron-aperture medicine release rate and the like with the accurate release of medicine diffusion permeability, medicine concentration gradient or discrete distribution in the device through the physical design of the skeleton shape and density of the inner sleeve and the outer sleeve, the porosity design of the inner sustained-release material, the material type of the sustained-release matrix, the material polymerization degree and viscosity, and the controlled release effect based on a phospholipid compound and a novel synthetic polymer.
(2) Meanwhile, the medicine can be modularized, personalized and matched with building block patterns according to the diagnosis of doctors, thousands of people and thousands of prescriptions can be made according to the requirements of patients with different weights, ages and treatment strengths, and personalized dosage modules of different medicines can be printed out in a 3D mode at any time according to prescription information and filled in the device.
(3) The manufacturing method is flexible and accurate: a loose and porous drug-loaded polymer inner drug-loaded tube is created by adopting a die method or 3D printing, drugs with different sizes and different doses can be adsorbed by adjusting the porosity, the process of forming drug-loaded gel is slow and mild, the traditional processes with strong destructiveness on the activity of the drugs, such as mechanical stirring, oil-water emulsification, high-temperature hot melting, high-pressure plasticizing forming and the like, do not exist, and compared with the thermoplastic method, the hot melting extrusion method and the drying method in multiple emulsion of the traditional implant, the activity retention of the biological drugs is greatly improved.
(4) Through the selection of the specifications of the semipermeable membranes of the drug release holes, the semipermeable membranes with different molecular weight cut-off can be replaced aiming at different types of drugs, and the personalized customization of commercial batches can be carried out.
(5) The inner drug-carrying tube of the device is made of PLGA material, and can slowly release drugs after forming gel, and then enter blood through the drug release hole of the semipermeable membrane. Compared with the open type gel injection (without an external cannula, a semipermeable membrane drug release hole for controlling the drug release and obvious burst release effect), the preparation method has fundamental improvement on the problems of drug burst release and large drug release fluctuation.
(6) Pore-forming agents (mannitol, trehalose, sucrose, glycine and the like) can be added into the inner drug-carrying tube of the device in the process of preparation or 3D printing to adjust the release rate and the release period of different drugs.
(7) The outer sleeve of the device is made of PLLA materials, and can not be degraded in the drug release period (within one year), and after 2 years, the outer sleeve is gradually degraded into endogenous materials harmless to human bodies, so that the injury to the human bodies caused by taking out the outer sleeve in a secondary operation is avoided.
(8) The outer sleeve A is internally provided with a prestored phospholipid compound organic solvent system (consisting of hydrogenated saturated soybean phospholipid, ethanol, methyl pyrrolidone NMP, propylene glycol and the like), is safe, nontoxic and harmless to human tissues, and before implantation, the drug column of the drug-carrying inner drug-carrying tube 2 is inserted into the outer sleeve A in a closed state to perform spontaneous infiltration and mixing to form instantaneous semi-fluid liquid gel which has certain fluidity, and then the organic solvent in the gel permeates through the controlled-release semi-permeable membrane holes to be absorbed by the human tissues, the liquid gel is gradually hardened, and after 1-2 days, the liquid gel is secondarily cured to form a stably-released drug-carrying solid drug rod; the different proportions of the phospholipid complex solvent can participate in the regulation and control of the release rate, and is non-toxic and harmless to human bodies.
(9) Through the 3D printing technology, the geometric dimension of the drug-loaded tube in the drug-releasing body, the void density of the matrix material of the framework, the framework strength, the distribution gradient, the porosity, the drug-loading ratio and the like can be flexibly controlled.
(10) The cocktail therapy of multiple medicines is realized in the same preparation by the traditional preparation method, which is difficult, each active substance is difficult to reach a target treatment part at the same time, and the activity of certain biological substances is difficult to store for a long time; some parts of dosing are the inside cavity of anomalous shape, and the device possesses the latent expansion serial product advantage of 3D printing, according to the shape of different positions, size, can in time obtain the 3D image with the mode of scanning, and then design the intelligent device of dosing to single patient's individualized demand, through the 3D printing of short time, after aseptic technique, can obtain a personalized product.
(11) The medicine property and long-time stability storage of nucleic acid, polypeptide, antibody and protein macromolecular medicines are obviously improved. Such drugs generally have the characteristics of poor stability, easy deformation of a spatial three-dimensional structure, and substantial loss of activity. Chemical or environmental changes in the manufacturing process may also result in a reduction or loss of biopharmaceutical activity. By utilizing the 3D low-temperature instantaneous forming printing technology, the whole preparation process can be carried out under the aseptic and low-temperature processes, and by continuously developing and adding the iterative bio-friendly printing ink substances (PLGA, phospholipid improved formula and the like), any harmful substances with toxic and side effects and environmental pollution are not added, the risk of inactivation of biological products is reduced, and the characteristics of the biological active substances such as patent medicine property, stability and long-term stable and controllable release are greatly improved.
Drawings
Fig. 1 is a structural diagram of an implantable drug delivery device provided by the present invention.
Fig. 2 is a design drawing of the implantable drug carrying device provided by the present invention.
Fig. 3 is a design drawing of an implantable drug delivery device provided by the present invention.
Wherein, 1, the outer sleeve; 2. an inner drug-loading tube; 3. a booster chamber; 4. adsorbing material; 5. nesting the inner casing pipe and the outer casing pipe; 6. hardening the framework; 7. a helical drug delivery channel; 8. a semipermeable membrane drug release hole; 9. an isolation film; 10. a locking device; 11. a penetration hole; 12. an organic solvent chamber.
Detailed Description
(1) The utility model provides a medicine carrying device is as shown in figure 1, includes in its concrete structure:
the outer sleeve 1 (propelling tube) + the inner medicine carrying tube 2 (medicine carrying tube) + the outer sleeve 1 and the inner medicine carrying tube 2 are locked by the inner sleeve and the outer sleeve nesting 5;
as shown in fig. 1, the right end of the outer sleeve 1 is an organic solvent chamber 12 (the organic solvent chamber 12 stores solvent), the main body of the outer sleeve 1 is also provided with an isolation film 9 made of PLLA material, and the left side is divided into a booster chamber 3, the thickness of the isolation film 9 is 0.5 mm;
(2) in addition, the medicine carrying device also comprises an inner medicine carrying tube 2, the inner medicine carrying tube 2 can be inserted into the organic solvent chamber 12, and when the medicine carrying device is not arranged in a body, the organic solvent in the outer sleeve 1 (propelling tube) and the medicine in the inner medicine carrying tube 2 (medicine carrying tube) are not contacted and are separately arranged, so the quality guarantee period of the medicine carrying device is far longer than that of a common solution type biological preparation, and can reach 2 years at normal temperature;
(3) the locking device 10 is used for fixing the relative positions of the outer sleeve 1 and the inner drug-carrying tube 2, before use, the locking device 10 is removed, the inner drug-carrying tube 2 is inserted into the outer sleeve 1 (the insertion direction is from one side of the organic solvent chamber 12 opposite to the isolating membrane 9), the PLLA isolating membrane 9 is punctured, the porous material of the inner drug-carrying tube 2 is contacted with the solvent and then reacts to form semi-liquid gel, a semi-permeable membrane drug release hole 8 is further arranged at one end of the inner drug-carrying tube 2 opposite to the isolating membrane 9, the organic solvent carrying active drug ingredients enters human tissues through the semi-permeable membrane drug release hole 8 at the right side to be absorbed, the drug gel is formed into a semi-solid state again, and the drug is slowly and uniformly released in the slow release framework.
The release rate is 1 year, and the release period can be adjusted within 3 months to 2 years by adjusting the formula, the size of the semi-permeable membrane gap, the material, the molecular weight, the viscosity and the like of the slow-release gel polylactic acid.
(4) The inner part of the outer sleeve 1 (propelling pipe) is divided into A, B two chambers (as shown in figure 1) by the isolating film 9, the left side A chamber is a boosting agent chamber which contains boosting agent (mannitol, sodium chloride, PEO and other water-absorbing and expanding materials); and the left side of the chamber A is also provided with a permeation hole 11;
(5) external water enters the chamber A from the permeation hole 11 on the left side of the chamber A and generates osmotic pressure with mannitol, PEO and other water-absorbing swelling materials, and after the isolating membrane 9 is punctured, the chamber A has higher osmotic pressure and the materials in the chamber B are gelatinized, so that the drug gel in the chamber B can be further pushed to be released to the semipermeable membrane drug release hole 8; forming slow osmotic flow in the direction of the permeation hole 11, the chamber A, the chamber B and the semipermeable membrane drug release hole 8 in sequence;
(6) the chamber A is 3mm long, the inner diameter is 3.3mm, the outer diameter is 3.45mm, and the left side is provided with 6 semi-permeable membrane openings 8; the pore diameter of the die hole is 25-80um and is blocked by HPMC-K100M or K200M;
(7) the right chamber B is a slow-release solvent chamber, and the interior of the slow-release solvent chamber is filled with an organic solvent; the specific structural parameters are as follows: the chamber B is 14mm long and 3.3mm in inner diameter;
(8) a, B the two chambers are physically separated by a PLLA separator; the thickness of the PLLA isolating film is 0.5 mm;
(9) the total length of the outer sleeve 1 is 18.5mm.
(10) The chamber B can store organic solvent, and the solvent can be composed of hydrogenated saturated soybean phospholipid, ethanol, methyl pyrrolidone NMP and propylene glycol (the proportion is most preferably 22%: 35%: 25%: 18%); modified other phospholipids such as soybean phospholipid, lecithin, cardiolipin, other natural phospholipids or synthetic phospholipids, etc.; besides the above organic solvents, other solvents which are harmless, safe and low-toxic to human body, such as tert-butyl alcohol, benzyl alcohol, glycerol, etc. can also be used;
(11) the organic solvent occupies 20-45% of the inner volume of the outer sleeve 1. The outer sleeve 1 can be obtained by a die method or a 3D printing method, and the material thereof can be PLLA. The outer casing is made of PLLA material, so that the outer casing has good biocompatibility and no irritation to human body, can be completely degraded into degradable products harmless to human body after being implanted into human body for 2 years, and does not need to be taken out through an operation. Alternatively, other materials can be used for the outer sleeve, such as: the functional polymer shell which is formed by a biodegradable magnesium alloy material, PCL/PDLLA copolymer, SAIB copolymer and the like in a single component or a mixture ratio of two or more than two components and has different drug release rates and different degradation periods. The above materials can reach the expected degradation rate of degradation after 2 years.
(12) The organic solvent in the B chamber is used for corroding the drug-containing column material (the drug column adsorbing material is PLGA, SAIB, PLG and other controlled degradable polymers) of the drug-carrying tube 2, and the saturated hydrogenated soybean phospholipid, methyl pyrrolidone, NMP, ethanol, propylene glycol and the like can be adopted.
(13) The inner drug-carrying tube 2 (drug storage tube) is of a honeycomb structure, the material of the inner drug-carrying tube can be selected from PLGA, SAIB and other degradable polymers, the inner drug-carrying tube can be obtained in a 3D printing mode, and polypeptide, antibody, protein and other macromolecular drug drugs can be adsorbed inside the inner drug-carrying tube. (length 21mm, diameter 3.05mm, semi-permeable membrane pore opening 20-280 nm). The porous structure of the inner drug carrying tube 2 can be manufactured by a 3D printing mode, the porosity of the porous surface can be 70-95%, the pore size can be 0.5-200um, and the pore density can be 100-5000 pieces/cm2(ii) a Can effectively adsorb active ingredients of the medicine; the diameter of interior medicine carrying pipe 2 is less than the internal diameter of outer tube 1, and interior medicine carrying pipe 2 can cup joint the inside to outer tube 1 to the inside of medicine carrying pipe 2 is equipped with sclerosis skeleton 6 in, and sclerosis skeleton 6 is used for puncturing the barrier film.
(14) After the inner drug-carrying tube 2 is manufactured, soaking the inner drug-carrying tube in a concentrated solution containing the drug, carrying out sufficient adsorption, then carrying out sterilization, and carrying out freeze drying to obtain a drug-containing inner cannula B; the medicine can be hormone, polypeptide, protein, nucleic acid and vaccine medicines, the biological medicine is a medicine with potential efficacy for treating diseases caused by growth hormone deficiency and the like, and other fields such as the weight-losing field, the beauty field, the Alzheimer's field, the mental disease field and the like need long-term treatment, in particular to an invasive treatment mode which has poor compliance caused by a drug administration mode which repeatedly generates irritation due to long-term injection. Preferably: the growth hormone deficient drug is at least one of hormone, polypeptide, protein and gene drug; further preferably: the medicine is at least one of human growth hormone, recombinant human growth hormone, polypeptide, protein and gene medicine or compound medicine composition.
(15) After the inner drug-carrying tube 2 absorbs the drug and is freeze-dried, a layer of PLGA polylactic acid film with the thickness of 0.2mm is wrapped outside the inner drug-carrying tube to prevent the drug from scattering or leaking from the honeycomb tissue;
(16) at the open end of the outer sleeve 1, an inner and outer sleeve nest 5 is provided. The inner sleeve 5 and the outer sleeve 5 are used for fixing the inner drug carrying tube 2.
The PLGA is adopted in the inner drug-carrying tube 2 for the purpose of being dissolved by the internal solvent 3, when the inner drug-carrying tube 2 is inserted into the outer sleeve 1, the solvent can slowly dissolve the inner drug-carrying tube 2 to form a semi-liquid gelatinous substance, so that the adsorbed active ingredients can form skeleton type slow release gel through liquefaction and solidification, and the drug is slowly released and released into the body through the semi-permeable membrane drug release hole 8 of the inner drug-carrying tube 2.
(17) The material of the semipermeable membrane may be cellulose acetate, polytetrafluoroethylene, etc., and the semipermeable membrane functions to slowly release the drug to the outside.
(18) The right side of the drug column (close to the drug release hole 8 of the semi-permeable membrane) of the inner drug-carrying tube 2 is in an internal curved spiral state (the thickness is 3mm, 12 curved spiral channels are arranged in the drug-carrying tube, and the channels are wound around the column core for 3-6 circles);
(19) due to the higher pressure generated by osmotic pressure expansion of the chamber A of the cannula 1, the built-in 12 channels with the winding of the curve spiral wound core can effectively reduce the drug release rate in order to prevent the formed drug gel column from being pushed out of the permeation hole at the right side of the inner drug carrying tube 2 caused by the higher pressure of the chamber A.
The device and the drug manufacturing process are as follows:
1) preparing a blank drug-containing inner drug-carrying tube 2 by a 3D printing method; adsorbing the medicine in the inner medicine carrying tube 2;
2) after the medicine is adsorbed by the inner medicine carrying tube 2 and freeze-dried, a layer of PLGA polylactic acid film with the thickness of 0.2mm is coated outside the inner medicine carrying tube; a semipermeable membrane plug is additionally arranged;
3) preparing an outer sleeve by a 3D printing method; filling osmotic pressure promoter in the chamber A and mixed organic solvent in the chamber B;
4) the B chamber is filled with a mixed solvent of PLGA with the concentration of 20% -56% or SAIB: NMP, ethanol, propylene glycol and phospholipid.
5) The filling amount of the solvent in the B chamber tube is (20-45% of the B chamber solvent is filled, and the specific filling amount is according to the porosity of the printed medicine-containing inner medicine-carrying tube 2); thermoplastic seal of PLLA film after filling
6) The contact surfaces of the outer sleeve and the inner sleeve are vertically connected together; and (4) additionally installing a chimeric locking device. Obtaining an integrated tube (organic solvent in the outer sleeve, biological medicine freeze-dried powder in the medicine column of the inner medicine-carrying tube 2 are stored separately without contact, the stability is greatly improved)
7) Placing the combined medicine device obtained in the step 6) in a professional sterile embedment device under a sterile condition, and storing;
8) just before use, the sterile insert is opened under sterile conditions: destroying and removing the embedded locking device 9, rotating the inner sleeve and the outer sleeve, mixing the drug-containing column of the inner drug-loaded tube 2 with the indoor slow-release solvent matrix B, and performing secondary dissolution and solidification;
9) after aseptic disinfection, the device is embedded in a specified part of a human body; after 24-36 hours, a therapeutic dose of the drug is available in the blood.
In addition, the monitor lantern ring shell is formed by PLLA and can be internally provided with a signal chip with a signal source transmitting function, the signal chip can be connected with a mobile terminal system, communication is achieved by installing a corresponding app program in the mobile terminal, and the external app is an android or OS system.
The outer sleeve 1 and the inner drug-carrying tube 2 can be manufactured by a traditional precision die method or can be manufactured individually by a 3D printing method, and different shapes (straight strip, arc, semicircle and the like) are adopted according to different indications, different drug-carrying quantities, different people and different injection embedding parts, so that the comfort of a user is improved, the physical irritation to muscle and dermal tissues is reduced, and the embedding discomfort is eliminated.
Example 1
The manufacturing process of the device and the medicine comprises the following steps:
1) manufacturing the inner drug carrying tube 2: with PLGA (fraction)12000-15000)1.26g, printing a blank drug column, a spiral drug release channel 7 (with an internal bent spiral state, a length of 3mm, 12 bent spirals in the 3-circle spiral drug release channel around the column core) and a permeable membrane pore plug (with 12 drug release pores, a pore diameter of 60um, a semi-permeable membrane material embedded in the column core of 77-14000 type, a cut-off molecular weight by a 3D printer according to a three-dimensional model drawing: more than 15000 semi-permeable membrane) 3 for standby; the porosity of the porous surface is 86 percent, the pore size is 53um, and the pore density is 2200/cm2；
2) Preparing a blank drug-containing inner drug-carrying tube 2; adsorbing the recombinant human growth hormone medicine in the inner medicine carrying tube 2; freeze-drying to obtain a medicine-containing tube; based on the recombinant human growth hormone, the total amount of the drug is 320 mg;
3) after the medicine adsorbed by the inner medicine carrying tube 2 is freeze-dried, the outer surface of the inner medicine carrying tube is wrapped by a layer of PLGA polylactic acid film with the thickness of 0.2 mm; the right end is not wrapped and is assembled with the spiral drug release channel 7 and the semipermeable membrane plug into a whole in sequence; the number of the spiral medicine releasing channels 7 is 12, the spiral medicine releasing channels wind the core of the column for 5 weeks, the diameter of the spiral body cylinder in the section direction is 3mm, and the inner diameter of the channels is 100 um.
4) Preparing an outer sleeve by a 3D printing method (comprising a boosting chamber A and a solvent chamber B, wherein the middle part is isolated by a PLLA film layer); the chamber A is 3mm long, the inner diameter is 3.3mm, the outer diameter is 3.45mm, and the left side is provided with 6 semi-permeable membrane openings 8; the aperture of the die hole is 25-80um and is blocked by HPMC-k 100M; the chamber B is 14mm long and 3.3mm in inner diameter;
5) filling an osmotic pressure promoter in the chamber A: 8mg of mannitol, 6mg of sodium chloride wrapped by 28mg of PLGA7525 (molecular weight 8000-12000) in a hot melting way, and 5.6mg of polyoxyethylene PEO5 with the molecular weight of 20-500 ten thousand as a boosting agent component; and 0.186 ml of mixed phospholipid compound organic solvent (22 percent to 35 percent to 18 percent of hydrogenated saturated soybean phospholipid, ethanol, methyl pyrrolidone NMP and propylene glycol) is filled in the chamber B, wherein the mixed phospholipid compound organic solvent contains 15 percent to 22mg of PLGA 85.
6) Thermoplastic sealing of the PLLA film after the solvent filling amount in the B chamber tube is finished; the thickness of the PLLA isolating film is 0.5 mm;
7) the contact surfaces of the outer sleeve and the inner sleeve are vertically connected together; the interlocking lock device 10 is additionally installed. Obtaining an integrated tube (phospholipid complex organic solvent system in the outer sleeve, biological medicine freeze-dried powder in the medicine column of the inner medicine-carrying tube 2 is stored separately without contact, the stability is greatly improved)
8) Placing the combined medicine device obtained in the step 7) in a professional sterile embedding device under a sterile condition, and storing (at 20-25 ℃);
9) just before use, the sterile insert is opened under sterile conditions: destroying and removing the embedded locking device 10, rotating the inner sleeve and the outer sleeve, mixing the drug-containing column of the inner drug-loaded tube 2 with the indoor slow-release solvent matrix B, and performing secondary dissolution for about 15 min;
10) after aseptic disinfection, the device is embedded in a specified part of a human body; after the water in the human body passes through the semi-permeable membrane permeation hole on the left side of the outer sleeve for 24-36 hours, the medicine with the therapeutic dose can be in the blood. This therapeutic effect may last for 12 months.
Example 2: the right side of the chamber A is not provided with a spiral medicine release channel.
1) Manufacturing the inner drug carrying tube 2: 1.26g of PLGA (molecular weight of 12000-15000) and 3 parts of structures of a blank drug column and a permeable membrane pore plug (12 drug release pores with the pore diameter of 60 mu m and a semipermeable membrane material of 77-14000 model and the trapped molecular weight of more than 15000 are embedded in the blank drug column and the permeable membrane pore plug) are printed by a 3D printer according to a three-dimensional model drawing for later use; the porosity of the porous surface is 86 percent, the pore size is 53um, and the pore density is 2200/cm2；
2) Preparing a blank drug-containing inner drug-carrying tube 2; adsorbing the recombinant human growth hormone medicine in the inner medicine carrying tube 2; freeze-drying to obtain a medicine-containing tube; based on the recombinant human growth hormone, the total amount of the drug is 320 mg;
3) after the medicine adsorbed by the inner medicine carrying tube 2 is freeze-dried, the outer surface of the inner medicine carrying tube is wrapped by a layer of PLGA polylactic acid film with the thickness of 0.2 mm; the right end is not wrapped and is assembled with the semipermeable membrane plug into a whole;
4) preparing an outer sleeve by a 3D printing method (comprising a boosting chamber A and a solvent chamber B, wherein the middle part is isolated by a PLLA film layer); the chamber A is 3mm long, the inner diameter is 3.3mm, the outer diameter is 3.45mm, and the left side is provided with 6 semi-permeable membrane openings 8; the pore diameter of the die hole is 25-80um and is blocked by HPMC-K100M or K200M; the chamber B is 14mm long and 3.3mm in inner diameter;
5) filling an osmotic pressure promoter in the chamber A: 8mg of mannitol, 6mg of sodium chloride wrapped by 28mg of PLGA7525 (molecular weight 8000-12000) in a hot melting way, and 5.6mg of polyoxyethylene PEO5 with the molecular weight of 20-500 ten thousand as a boosting agent component; the chamber B is filled with 0.186 ml of mixed phospholipid compound organic solvent (22 percent of hydrogenated saturated soybean phospholipid, 35 percent of ethanol, 25 percent of methyl pyrrolidone NMP and 18 percent of propylene glycol) which contains 22mg of PLGA85 or SAIB.
6) Thermoplastic sealing of the PLLA film after the solvent filling amount in the B chamber tube is finished; the thickness of the PLLA isolating film is 0.5 mm;
7) the contact surfaces of the outer sleeve and the inner sleeve are vertically connected together; the interlocking lock device 10 is additionally installed. Obtaining an integrated tube (phospholipid complex organic solvent system in the outer sleeve, biological medicine freeze-dried powder in the medicine column of the inner medicine-carrying tube 2 is stored separately without contact, the stability is greatly improved)
8) Placing the combined medicine device obtained in the step 7) in a professional sterile embedding device under a sterile condition, and storing (at 20-25 ℃);
9) just before use, the sterile insert is opened under sterile conditions: destroying and removing the embedded locking device 10, rotating the inner sleeve and the outer sleeve, mixing the drug-containing column of the inner drug-loaded tube 2 with the indoor slow-release solvent matrix B, and performing secondary dissolution for about 15 min;
10) after aseptic disinfection, the device is embedded in a specified part of a human body; after the water in the human body passes through the semi-permeable membrane permeation hole on the left side of the outer sleeve for 24-36 hours, the medicine with therapeutic dosage can be in the blood, and because the spiral medicine release channel module with no spiral channel is arranged in the device, the medicine release behavior completely different from that of the implantation device with the spiral medicine release channel is generated. The treatment effect can be short in duration and is significantly lower than that of a device with a spiral drug release channel.
Comparative example 1: the differences from example 1 are: the solvent chamber B is not loaded with a composite organic solvent.
1) Manufacturing the inner drug carrying tube 2: using PLGA (molecular weight of 12000-The molecular weight retention is: more than 15000 semi-permeable membrane) 3 for standby; the porosity of the porous surface is 86 percent, the pore size is 53um, and the pore density is 2200/cm2；
2) Preparing a blank drug-containing inner drug-carrying tube 2; adsorbing the recombinant human growth hormone medicine in the inner medicine carrying tube 2; freeze-drying to obtain a medicine-containing tube; based on the recombinant human growth hormone, the total amount of the drug is 320 mg;
3) after the medicine adsorbed by the inner medicine carrying tube 2 is freeze-dried, the outer surface of the inner medicine carrying tube is wrapped by a layer of PLGA polylactic acid film with the thickness of 0.2 mm; the right end is not wrapped and is assembled with the semipermeable membrane plug into a whole;
4) preparing an outer sleeve by a 3D printing method (comprising a boosting chamber A and a solvent chamber B, wherein the middle part is isolated by a PLLA film layer); the chamber A is 3mm long, the inner diameter is 3.3mm, the outer diameter is 3.45mm, and the left side is provided with 6 semi-permeable membrane openings 8; the pore diameter of the die hole is 25-80um and is blocked by HPMC-K100M or K200M; the chamber B is 14mm long and 3.3mm in inner diameter;
5) filling an osmotic pressure promoter in the chamber A: 8mg of mannitol, 6mg of sodium chloride wrapped by 28mg of PLGA7525 (molecular weight 8000-12000) in a hot melting way, and 5.6mg of polyoxyethylene PEO5 with the molecular weight of 20-500 ten thousand as a boosting agent component; the B chamber was filled with mixed phospholipids (40.92 mg of hydrogenated saturated soybean phospholipids) but did not contain a complex organic solvent.
6) Thermoplastic sealing of the PLLA film after the solvent filling amount in the B chamber tube is finished; the thickness of the PLLA isolating film is 0.5 mm;
7) the contact surfaces of the outer sleeve and the inner sleeve are vertically connected together; the interlocking lock device 10 is additionally installed. Obtaining an integrated tube (the outer sleeve does not contain a lipid complex organic solvent system, and the biological medicine freeze-dried powder in the medicine column of the inner medicine-carrying tube 2 is stored separately and does not contact with the outer sleeve);
8) placing the combined medicine device obtained in the step 7) in a professional sterile embedding device under a sterile condition, and storing (at 20-25 ℃);
9) just before use, the sterile insert is opened under sterile conditions: breaking and removing the embedded locking device 10, rotating the inner sleeve and the outer sleeve, and mixing the medicine-containing column of the inner medicine-carrying pipe 2 with the substance in the chamber B;
10) after aseptic disinfection, the device is embedded in a specified part of a human body; after the water in human body passes through the semi-permeable membrane permeation hole on the left side of the outer sleeve for 24-36 hours, the medicine with therapeutic dose can be in the blood, and because the device does not contain the compound organic solvent, the drug release behavior completely different from that of the device normally containing the compound organic solvent is generated. In vivo animal data show: the sample of the comparative example 1 has very fast release speed and poor slow release effect, and the treatment effect is obviously lower than that of a device containing an organic solvent in the prescription.
Comparative example 2
The difference from example 1 is that: the booster is not added to the booster chamber A, but the same organic solvent as used in the chamber B is used instead.
Secondly, the in vivo release process of the medicine: animal experiment (Bama miniature pig hip embedding control experiment)
Growth hormone is a glycoprotein hormone secreted by anterior pituitary, has a molecular weight of 21500, is an important hormone for regulating substance metabolism, and can promote growth of infants and children. Growth Hormone Deficiency (GHD) is caused by insufficient or deficient secretion of growth hormone, so that the normal development of children cannot be maintained, the development of children is short, and the normal physiological and psychological development of children is influenced. For the children with the short stature, factors such as heredity, environment, nutrition, endocrine and the like are possible to be the disease factors, and the deficiency of GH is common. Clinically, the differential diagnosis of the infant suffering from GHD is usually carried out by a growth hormone stimulation experiment. The growth of children is influenced by genetic, environmental and nutritional factors, and growth hormone deficiency is a common endocrine cause causing growth retardation of children, so that the serum GH detection is an important clinical diagnosis basis for GHD detection. Under normal conditions, GH is released in pulses, with most secretion during sleep at night, less secretion during the day, and lower measurements in the morning on an empty stomach. According to literature reference, the serum (GH) level of normal adolescent children is significantly different from that of children diagnosed with growth hormone deficiency (growth hormone deficiency) by conventional growth hormone challenge test. The small Bama pigs which are close to human tissues are taken as a substitute research object, and the difference of the device on the release in the human body and the stability of the drug in the blood at different time points are preliminarily evaluated.
The detection method comprises the following steps:
enzyme-linked immunosorbent assay: detecting the level of growth hormone in adult Bama miniature pigs by an ELISA method;
and (3) inspecting materials:
1.1 Instrument: enzyme-linked immunosorbent assay (Anthos, Austria, 2010 type Labtec Instruments)
1.2 reagent syntron Bioresearch, Inc. Microwell HGHELA
1.3 example 1 drug loaded recombinant human growth hormone implant stick, example 2, control 1, control 2, each of the blanks (sterile package)
1.4 sample collection and pretreatment:
the devices were placed in the posterior gluteal position of 5 4-month old Bama piglets, and after topical treatment with local anesthetic, the drug-containing devices (one year sustained release), example 2 group, control 1, control 2 and drug-free blank devices were embedded approximately 3.5 mm subcutaneously, respectively. The affected part is buried for 24 hours and then is observed to see whether local bleeding, cyanosis and inflammatory reaction exist. Feeding 5 experimental pigs respectively according to the same conditions, taking 8 milliliters of venous blood on the third day, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months and 12 months after embedding the device, centrifuging, refrigerating for storage and detection. The concentration difference of recombinant human growth hormone in the blood sample was measured by ELISA method to confirm whether the drug was released into the in vivo blood of the experimental pig.
The specific method comprises the following steps: collecting venous blood according to a specified time point under the state of no feeding in the first day and the evening and no eating in the morning, then administering clonidine medicine, then respectively collecting blood in 30min, 60min, 90min and 120min, separating serum, and freezing and storing; arginine stimulation was given the next day and blood was collected as in the first day method.
By adopting a high-specificity enzyme immunoassay method, the correlation coefficient of a standard curve measured each time is more than 99 percent, and the result conforms to the enzyme immunoassay quality control standard.
2, results:
2.1 clonine stimulated, arginine stimulated serum GH assay results for the group of example 1;
2.2 clonine stimulated, arginine stimulated serum GH assay results for example 2 group;
2.3 comparative example 1 group clonidine stimulated, arginine stimulated serum GH assay results;
2.4 results of clonidine-stimulated and arginine-stimulated serum GH assay in control example 2;
2.5 blank control group clonidine stimulated and arginine stimulated serum GH determination results;
clonidine stimulated serum GH assay results-table 1 (day three)
Arginine stimulated serum GH assay results-table 2 (third day)
Clonidine stimulated serum GH assay results-table 3 (first week)
Arginine-stimulated serum GH assay results-table 4 (week one) 0.77 ± 0.381.52 ± 0.71
Clonidine stimulated serum GH assay results-table 5 (second week)
Arginine stimulated serum GH assay results-table 6 (second week)
Clonidine stimulated serum GH assay results-table 7 (first month)
Arginine stimulated serum GH assay results-table 8 (first month)
Note: the devices of the example 2 (without helical drug delivery channel) and the control 1 (without complex organic vehicle) groups terminated the two groups of experiments because they released the drug too quickly in vivo, resulting in too high a drug concentration in the experimental animals, which was far above the hormone level in normal pigs.
Clonidine stimulated serum GH assay results-table 9 (february)
Arginine stimulated serum GH assay results-table 10 (february second)
Clonidine stimulated serum GH assay results-table 11 (march three)
Arginine stimulated serum GH assay results-table 12 (third month)
Clonidine stimulated serum GH assay results-table 13 (april)
Arginine stimulated serum GH assay results-table 14 (fourth month)
Clonidine stimulated serum GH assay results-table 15 (sixth month)
Arginine stimulated serum GH assay results-table 16 (sixth month)
Clonidine stimulated serum GH assay results-table 17 (ninth month)
Arginine stimulated serum GH assay results-table 18 (ninth month)
Clonidine stimulated serum GH assay results-table 19 (december)
Arginine stimulated serum GH assay results-table 20 (december)
And (4) test conclusion: the level of growth hormone in blood of 5 bama miniature pigs respectively embedded with different drug-loaded devices and without the drug-loaded devices is obviously different; for mini pigs embedded with drug-loaded devices: growth hormone levels on days three, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 6 months, 9 months, and 12 months, were at more balanced and stable levels (high drug concentration at individual points, possibly related to fluctuations in the test after sampling), indicating that the drug delivery device was within a 12 month period: the recombinant human growth hormone medicine is released stably and at a constant speed.
Example 2 and comparative example 1 due to the lack of critical compositions in the apparatus respectively: the spiral drug release channel and the organic solvent cause the too fast drug release, which is not suitable for further development. A comparison of example 1 and control 2 shows that in the absence of a booster, osmotic pressure is not effectively built up, resulting in an organic vehicle that does not deliver the drug well into the body.
Claims (10)
1. A long-acting smart implantable drug delivery device, comprising:
the inner part of the outer sleeve (1) is divided into an A cavity and a B cavity by an isolating membrane (9); the cavity A is used for storing boosting agent; the cavity B is an organic solvent chamber for storing organic solvent;
the inner drug-carrying tube (2) can be nested in the cavity B of the outer sleeve (1); the inner drug-carrying tube (2) comprises a columnar adsorbing material which is used for adsorbing active drug components;
the end part of the inner drug-carrying tube (2) back to the cavity B is also provided with a semi-permeable membrane drug release hole (8), and a semi-permeable membrane is arranged in the semi-permeable membrane drug release hole (8) and is used for releasing active drug components outwards.
2. The long-acting smart implantable drug-carrying device according to claim 1, wherein a penetration hole (11) is further opened on the outer surface of the cavity A.
3. The long-acting smart implantable drug-carrying device of claim 1, further comprising: the inner sleeve and the outer sleeve are nested (5) which is arranged at the end part of one side of the cavity B of the outer sleeve (1) and is used for fixing the outer sleeve (1) and the inner drug-carrying tube (2).
4. The long-acting smart implantable drug-carrying device of claim 1, further comprising: and the hardening framework (6) is positioned inside the adsorbing material, and the hardening framework (6) is used for puncturing the isolating membrane (9).
5. The long-acting smart implantable drug-carrying device of claim 1, further comprising: the locking device (10) is used for fixing the outer sleeve (1) and the inner drug-carrying tube (2) and preventing the inner drug-carrying tube (2) from puncturing the isolating membrane (9).
6. The long-acting smart implantable drug-carrying device according to claim 1, wherein the locking device (10) is detachably connected to the outer cannula (1) and the inner drug-carrying tube (2).
7. The long-acting intelligent implantable drug-carrying device according to claim 1, wherein the surface porosity of the adsorbing material is 70-95%, the pore size is 0.5-200um, and the pore density is 5000 + cm 100.
8. The long-acting smart implantable drug-carrying device according to claim 1, wherein the outer surface of the adsorption material is coated with a PLGA polylactic acid film.
9. The long-acting intelligent implantable drug-carrying device according to claim 1, wherein a spiral drug release channel (7) is further provided inside the adsorption material; the spiral medicine releasing channel consists of 2-10 channels around the column core in 2-20 number and cylinder section of 1-10mm diameter.
10. The long-acting intelligent implantable drug-carrying device according to claim 1, wherein in one embodiment, the outer cannula (1) and the inner cannula (2) are made of one of PLGA, biodegradable magnesium alloy material, PCL/PDLLA copolymer, SAIB copolymer; the material of the semipermeable membrane is cellulose acetate or polytetrafluoroethylene; the organic solvent is selected from one of hydrogenated saturated soybean phospholipid, ethanol, methyl pyrrolidone NMP or propylene glycol; the boosting agent is selected from mannitol, sodium chloride or PEO.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023216509A1 (en) * | 2022-05-12 | 2023-11-16 | 北京理贝尔生物工程研究所有限公司 | Implant prosthesis |
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