CN112023114A - Lacrimal canaliculus obstruction core material for lacrimal canaliculus embolism operation and preparation method thereof - Google Patents

Abstract

The invention relates to the technical field of medical instruments, in particular to a lacrimal duct obstruction core material for a lacrimal duct embolism operation and a preparation method thereof. The lacrimal canaliculus obstruction core material is in a liquid state below a critical temperature and in a glue solid state above the critical temperature, and is prepared from the following raw materials: hyaluronic acid, temperature-sensitive polymers and degradable polymers. The lacrimal canaliculus blocking core material is beneficial to the application of minimally invasive or needle head surgery, and greatly reduces the discomfort caused by the foreign body sensation of the affected part in the using process; on the other hand, the utility model increases the time of remaining in the human body cavity or the affected part, achieves the effect of supporting the lacrimal duct and completely embolizing in a certain time, and has solubility. The lacrimal duct obstruction core of the invention is suitable for the treatment of lacrimal passages of different patients, and the shape of the lacrimal duct obstruction core can deform along with the bending of the lacrimal passage, thereby being effectively attached to the lacrimal duct, preventing the obstruction core from loosening and generating effective embolism effect.

Description

Lacrimal canaliculus obstruction core material for lacrimal canaliculus embolism operation and preparation method thereof

Technical Field

The invention relates to the technical field of medical instruments, in particular to a lacrimal duct obstruction core material for a lacrimal duct embolism operation and a preparation method thereof.

Background

The xerophthalmia is a civilization disease (accounting for 10-15% of the population of adults) which troubles modern people, and common symptoms comprise dry eyes, photophobia, lacrimation, foreign body sensation, stabbing pain, eye-opening difficulty, eye itching, eye discomfort and the like. According to the classification of lacrimal gland secretion function, dry eye can be classified into two major categories of insufficient lacrimal secretion (water deficient dry eye) and excessive lacrimal evaporation (evaporative dry eye).

Medical treatment can be adopted in the early stage of dry eye, but when the medical treatment and the medicine cannot cure or the symptoms are serious, surgical treatment is required for treatment, and in the common surgical treatment of dry eye patients, lacrimal duct embolism is applied to dry eye with water deficiency. At present, the lacrimal duct embolization avoids the permanent embolization by electric burning as much as possible, but the lacrimal duct blocking core made of different materials is implanted into the lacrimal duct to seal the lacrimal duct discharge pipeline, so as to achieve the effects of storing lacrimal water in the eye socket, reducing water loss and further improving xerophthalmia.

At present, the comfort level of the commonly used silicone rubber particle embolus in the lacrimal duct obstruction core is high, but the patient is unlikely to accept the plug if the plug is permanently placed in the lacrimal duct, the lacrimal duct obstruction core needs to be washed out through an operation in the later stage, the use is inconvenient, and the risk of inflammation caused by the dislocation of the obstruction core exists in the use process. Temporary lachrymal occlusive cores such as collagen micelles can automatically dissolve after being placed in the lachrymal duct for several weeks, but some patients can also cause eye inflammation due to incomplete breakdown of the micelles.

In addition, the eyes are quite sensitive organs, and patients are easy to feel foreign body sensation and discomfort of the eyes during the embolization; meanwhile, most lacrimal duct obstruction cores are solid tubular objects, and the lacrimal canaliculus of a human body is not in a straight tubular structure, so that a plurality of lacrimal duct obstruction cores cannot be effectively attached to the lacrimal duct, and the obstruction cores are easy to loosen and lose the effective embolism effect.

Disclosure of Invention

In view of the above disadvantages of the prior art, the present invention aims to graft a medical procedure as soon as possible, and solves the technical problems of inconvenient use of lacrimal canaliculus obstruction core, inability of effective attachment to lacrimal canaliculus, poor experience of patients, etc. in the prior art by using high molecular weight hyaluronic acid commonly used in medical procedures as a matrix and using biodegradable materials and temperature sensitive materials as a mixture to form a lacrimal canaliculus obstruction core material, and using the lacrimal canaliculus obstruction core material in lacrimal canaliculus embolization.

In order to achieve the above objects and other related objects, the present invention adopts the following technical solutions:

in one aspect, the present invention provides a lacrimal canaliculus obstruction core material for lacrimal canaliculus embolization, the lacrimal canaliculus obstruction core material being injectable in a liquid state below a critical temperature and in a gelled state above the critical temperature

The liquid state refers to that the lacrimal canaliculus obstruction core material is a flowing liquid below a critical temperature, and is beneficial to injection and beating; the term "gelatinous" refers to a high molecular polymer which is plastic at a temperature above the critical temperature of the lacrimal canaliculus obstruction core material, and the shape of the high molecular polymer can deform along with the bending of the lacrimal passage, keep the shape of the lacrimal passage, effectively fit with the lacrimal duct, and have no edges and corners, so the material has low damage degree on eye tissue cells.

Optionally, the lacrimal canaliculus obstructing core material comprises hyaluronic acid, a temperature-sensitive polymer and a degradable polymer; wherein the concentration of the hyaluronic acid in the lacrimal canaliculus obstruction core material is 0.001-5% (w/v), the concentration of the thermo-sensitive polymer in the lacrimal canaliculus obstruction core material is 12-30% (w/v), and the concentration of the degradable polymer in the lacrimal canaliculus obstruction core material is 5-45% (w/v).

Optionally, the hyaluronic acid has a molecular weight of 1000-15000 KDa.

Optionally, the temperature-sensitive polymer is one or more of a copolymer of polyoxyethylene and polyoxypropylene, pluronic F38, pluronic F68, pluronic F77, pluronic F87, pluronic F88, pluronic F127, polyisopropylacrylamide, gelatin, and chitin.

Among them, the temperature sensitive polymer is an intelligent polymer capable of responding to a temperature stimulus. Under the change of external temperature, the temperature-sensitive polymer can generate corresponding changes of physical structure and chemical property, and the swelling change is often obvious in the response process. The solubility change of the temperature-sensitive polymer after being heated is in a rule which is contrary to that of general substances, namely, when the temperature is increased to a specific temperature (namely, a critical temperature), the solubility of the polymer is reduced. According to the characteristics, the matrix or the medicament is kept in a liquid state before application, so that the application of minimally invasive or needle surgery is facilitated, the matrix or the medicament is converted into a gel state when entering an affected part of a human body, the gel state has the function of transient molding, the expansion and supporting effects are strengthened, and the maladaptation caused by the foreign body sensation of the affected part is greatly reduced.

Optionally, the degradable polymer is one or more of poly-L-lactic acid, poly-dl-lactic acid, poly-glutamic acid, polycaprolactone, and polycaprolactone polyol. Generally, hyaluronic acid is metabolized by contacting with body fluid after entering a human body, so that hyaluronic acid is clinically considered to be naturally degradable in the human body, and the hyaluronic acid is combined with a high-molecular polymer to slow down the metabolism. Therefore, the invention adopts the hyaluronic acid as the substrate and the biodegradable material as the mixture to form the degradable polymer, which can prolong the degradation time of the mixture, inhibit the action of the human body on the degrading enzyme of the hyaluronic acid and increase the time for the hyaluronic acid to be remained in the cavity or the affected part of the human body besides the configuration of the bulk material. Therefore, the lacrimal duct obstruction core material prolongs the support and curative effect period of the material, has the effects of supporting and completely embolizing the lacrimal duct within a certain period of time, and can be completely degraded finally. The lacrimal canaliculus obstruction core overcomes the defects in the prior art, can be conveniently applied and safely and stably treated for xerophthalmia, and can prevent lacrimal passage from being narrowed after acid-base burn.

In the actual use process, after the lacrimal canaliculus obstruction core material is implanted into the lacrimal canaliculus of a patient, the lacrimal canaliculus obstruction core material forms a glue strip with the length of 2-20 mm and the diameter of 0.1-1 mm (according to the size of the lacrimal canaliculus of the human body), namely the lacrimal canaliculus obstruction core. The core blocking material is suitable for treating lacrimal passages of different patients, and after the core blocking material is implanted into the lacrimal passages, the shape of the lacrimal canaliculus core blocking can deform along with the bending of the lacrimal passages, so that the shape of the lacrimal passages is maintained, the core blocking material can be effectively attached to the lacrimal passages, the core blocking is prevented from loosening, and an effective embolism effect is generated; in addition, because the lacrimal duct obstruction core is made of polyester medical polymer material, the material can not be adhered with new cells, therefore, the tissue cells proliferated after burn can not be adhered on the lacrimal duct obstruction core, and the effect of preventing the lacrimal duct from narrowing is obvious; the lacrimal canaliculus resistance core is firmly contacted with the lacrimal passage, further can not slide down to the lacrimal passage, is not easy to rub eyes and fall out, and has fixed position.

Further optionally, the canalicular obstructing material further comprises a pharmaceutical and/or nutritional factor. The doctor can mix the medicine and/or the nutritional factors into the lacrimal canaliculus blocking core material according to the actual demand of the patient, then the medicine and/or the nutritional factors are implanted into the lacrimal canaliculus and released by the slow release effect to be absorbed by eyes, and the treatment effect on the acid-base burn symptom and the dry eye disease of the eyes can be further improved. Of course, other substances may be mixed into the lacrimal canaliculus obstruction material during actual use according to actual needs, and it is understood that the difference of the mixed substances does not constitute the technical feature different from the present invention.

Preferably, the concentration of the hyaluronic acid in the lacrimal canaliculus obstruction core material is 0.01-2% (w/v), the concentration of the thermo-sensitive polymer in the lacrimal canaliculus obstruction core material is 12-20% (w/v), and the concentration of the degradable polymer in the lacrimal canaliculus obstruction core material is 5-20% (w/v).

On the other hand, the invention also provides a preparation method of the lacrimal duct obstruction core material for the lacrimal duct embolism operation, which comprises the following steps:

s1: dissolving hyaluronic acid powder in Phosphate Buffered Saline (PBS);

s2: dissolving temperature-sensitive polymer powder in PBS;

s3: dissolving temperature-sensitive polymer powder in PBS;

s4: mixing the solutions obtained in the steps S1-S3 at 0-12 ℃, and standing for 12-36 hours to obtain a lacrimal canaliculus obstruction core material;

wherein the concentration of the hyaluronic acid in the lacrimal canaliculus obstruction core material is 0.001-5% (w/v), the concentration of the thermo-sensitive polymer in the lacrimal canaliculus obstruction core material is 12-30% (w/v), and the concentration of the degradable polymer in the lacrimal canaliculus obstruction core material is 5-45% (w/v).

Preferably, the concentration of the hyaluronic acid in the lacrimal canaliculus obstruction core material is 0.01-2% (w/v), the concentration of the thermo-sensitive polymer in the lacrimal canaliculus obstruction core material is 12-20% (w/v), and the concentration of the degradable polymer in the lacrimal canaliculus obstruction core material is 5-20% (w/v).

Optionally, the solution in the steps S1-S3 is dissolved in a vortex manner under the condition of 500-2000 rpm by a small oscillator or a magnet stirrer.

It should be noted that the lacrimal canaliculus obstruction core material of the present invention needs to be treated endlessly before use, and the aseptic treatment method can be ultraviolet irradiation sterilization.

As described above, the lacrimal duct obstruction core material for the lacrimal duct embolism operation and the preparation method thereof provided by the invention have the following beneficial effects:

(1) the lacrimal canaliculus blocking core material is a flowing liquid below the critical temperature, namely, the material can be injected, thereby being beneficial to the application of minimally invasive or needle surgery and greatly reducing the foreign body feeling and the uncomfortable feeling of patients; the high molecular polymer which forms plasticity above the critical temperature is transformed into gel after entering a human body, has a transient shaping function, strengthens the expansion force and the supporting force, does not have any edges and corners, and has low damage degree to eye tissue cells.

(2) The lacrimal duct resistance core is suitable for treatment of lacrimal passages of different patients, and the resistance core material is implanted into the lacrimal passages to form the lacrimal duct resistance core, the shape of the resistance core can deform along with the bending of the lacrimal passages, and the shape of the lacrimal passages is kept, so that the resistance core can be effectively attached to the lacrimal ducts, the resistance core is prevented from loosening, and an effective embolism effect is generated; in addition, because the lacrimal duct obstruction core is made of polyester medical polymer material, the material can not be adhered with new cells, therefore, the tissue cells proliferated after burn can not be adhered on the lacrimal duct obstruction core, and the effect of preventing the lacrimal duct from narrowing is obvious; the lacrimal canaliculus resistance core is firmly contacted with the lacrimal passage, further can not slide down to the lacrimal passage, is not easy to rub eyes and fall out, and has fixed position.

(3) The lacrimal duct obstruction core material adopts degradable materials, can prolong the degradation time of the mixture by the configuration of the body material, can inhibit the action of the human body on the degrading enzyme of the hyaluronic acid, increases the time for the hyaluronic acid to be remained in the cavity or the affected part of the human body, achieves the effects of supporting the lacrimal duct and completely embolizing within a certain time, and has solubility and short-acting property.

(4) The core blocking material can be mixed with medicines and/or nutritional factors and the like, and can be absorbed by eyes after being released through a slow release effect, so that the symptoms of dry eye and acid-base burn of the eyes can be better treated.

Drawings

FIG. 1 is a graph of the gelling reaction of the lacrimal canaliculus occlusion material of the present invention under effective temperature conditions;

FIG. 2 is a viscoelastic diagram of a lacrimal canaliculus occlusion material under temperature change in accordance with the present invention;

FIG. 3 is a graph of an in vitro embolic support experiment of a lacrimal canaliculus occlusion material of the present invention;

FIG. 4 is a graph showing an analysis of the amount of lacrimal secretion in rabbits of a control group and an experimental group, which are used in example 5 of the present invention;

FIG. 5 is a photograph of a rabbit corneal tissue stained section of a control group and an experimental group in example 5 of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The experimental procedures described in the following examples are conventional unless otherwise specified, and the reagents and materials are commercially available without further specification. The focus of the present invention is on the selection of the components of the lacrimal canaliculus obstruction core material, and the content of the components can be specifically adjusted by those skilled in the art according to the actual needs within the scope of the present disclosure, and the preferred technical solutions are exemplified in the embodiments of the present invention.

Example 1: preparation of lacrimal duct core-blocking material

(1) Dissolving 0.01-2% (w/v) hyaluronic acid powder (molecular weight 1000-15000 KDa) in Phosphate Buffered Saline (PBS);

(2) dissolving 12-20% (w/v) Pluronic F127 powder in PBS;

(3) dissolving 5-20% (w/v) of polyglutamic acid powder in PBS;

(4) and (3) dissolving the three solutions in the steps (1) to (3) in a vortex mode by using a small oscillator or a magnet stirrer at 500-2000 rpm, fully mixing and stirring at 0-12 ℃ after dissolving, and standing for 12-36 hours to obtain the lacrimal canaliculus obstruction material.

Example 2: temperature dependence of curing of the conversion coating

As shown in fig. 1, a graph of the relationship between temperature and curing of the conversion glue is shown, wherein the abscissa of the graph is the mass concentration of the temperature-sensitive polymer in the system, the ordinate is the critical temperature, and above the critical temperature, the lacrimal duct resistance core material is in a glue solid state (gel); below the critical temperature, the canalicular obstructing material is in an injectable liquid state.

Example 3: rheological property test of lacrimal duct resistance core

The rheological characteristics of the lacrimal duct obstruction core material are analyzed by a Rheometer (TA instrument, AR2000ex system), and the specific experimental method comprises the following steps:

after loading the lacrimal canaliculus obstruction core material prepared in example 1 on the center of a 20mm flat plate, applying rotational vibration, first analyzing the viscosity coefficient (G') and the elasticity coefficient (G ") of the sample at a low temperature of 4 ℃ for 4 minutes; gradually raising the testing temperature of the rheometer to 37 ℃ (4 ℃ in 0-360 seconds, 15 ℃ in 480-720 seconds, 25 ℃ in 840-1080 seconds and 37 ℃ in 1080 seconds), analyzing the viscosity coefficient (G ') and the elastic coefficient (G') of the sample after the testing temperature is stable, and continuing the body temperature analysis stage for 50 minutes. The experimental result is shown in fig. 2, and it can be seen from the figure that the lacrimal canaliculus obstruction core material prepared in example 1 has better viscoelasticity, and with the increase of temperature, a better viscous and jelly-like stable elastomer is generated, and the embolization and supporting effects on the lacrimal canaliculus can be achieved.

Example 4: lacrimal duct obstruction core external plug support test

In the embodiment, the lacrimal canaliculus is simulated by a glass capillary with the pipe diameter of 1mm in an in-vitro environment, and the artificial tear is simulated by a commercially available artificial tear or PBS (phosphate buffered saline) so as to verify the embolization effect of the lacrimal canaliculus obstruction core on the lacrimal canaliculus.

(1) Dividing the glass capillary tube for simulating the lacrimal canaliculus of the human body into four groups, wherein the three groups comprise a control group and an experimental group which are respectively marked as a group A, a group S, a group R and a group P, wherein the group A, the group S and the group R are control groups, and respectively injecting three commercially available artificial tears into the glass capillary tube to simulate human tears; the P group is an experimental group, and PBS is injected to simulate human tears. The specific information of each group is as follows:

(2) implanting the lacrimal canaliculus blocking core material prepared in the example 1 into 4 groups of glass capillaries in the step (1) at the temperature of below 20 ℃, and controlling the lengths of the cementing strips in each group of glass capillaries to be equal;

(3) and (3) placing the 4 groups of glass capillaries in the step (2) into test tubes for storage, carrying out the experiment under the conditions of normal temperature and no tube sealing, adding artificial tears along with the artificial tears due to temperature evaporation in the process, and taking pictures of all groups of test tubes for recording.

As can be seen from fig. 3, the lacrimal canaliculus obstruction core material prepared in example 1 forms a glue strip shape according to the shape of the capillary after being implanted into the glass capillary and heated, and can effectively maintain the plug supporting effect for more than 18 days. Wherein, the experimental group adopts PBS to simulate artificial tears, and the PBS is the solution matrix of the invention, so the experiment can prove that the invention can still generate effective supporting embolism effect by using the miscible solvent to test; the three groups of control groups respectively adopt different popular commercial or ophthalmologically recommended artificial tears (A: Alcon (Elkang), S: Santen (Shentian) and R: Rohto (London)), so the experiment can prove that the lacrimal duct obstruction core still has effective supporting embolism under the flushing of a plurality of artificial tears.

Example 5: lacrimal canaliculus obstruction core internal plug support test

This example observes the effect of the lacrimal canaliculus occlusion material prepared in example 1 on the embolic support of lacrimal canaliculus by establishing a model of dry eye in an experimental animal (rabbit). The specific experimental steps are as follows:

(1) establishment of a model of experimental animal (rabbit) xerophthalmia

Experimental animals:

new Zealand white rabbits, male, with a weight of 1.8-2.0 kg, were housed individually in an environment with constant temperature and relative humidity (temperature: 24 + -2 deg.C; humidity: 50-60%), and were provided with drinking water and standard food freely. All animal experimental protocols were in accordance with the guidelines of the animal protection and use committee of university of zhejiang and with the resolution of the association for vision and ophthalmology (ARVO).

The specific experimental method comprises the following steps:

1.0% atropine sulfate ophthalmic gel (Atropina Lux, Allergan, Italy) was added to a l mL needle-free sterile syringe and implanted into the lower conjunctival sac of each rabbit at a dose of 0.1mL gel/body three times a day (8: 00 am; 12:00 am; 4:00 pm) for 7 days to create a dry eye-like model.

(2) Dividing the white rabbits successfully built with the xerophthalmia model into two groups at random, wherein each group comprises 3 rabbits, namely a control group and a test group;

(3) PBS was injected into the three rabbit lacrimal passages of the control group, and the lacrimal canaliculus blocking material prepared in example 1 was injected into the three rabbit lacrimal passages of the experimental group;

(4) observing average amount secretion of tears in the lacrimal passages of the rabbits of the experimental group and the control group for 7 consecutive days;

(5) randomly taking one rabbit from the experimental group and the control group to be used as a corneal tissue staining section on the seventh day of the experiment;

(6) and (5) analyzing an experimental result.

The above experimental results were specifically analyzed as follows:

FIG. 4 is a graph showing an analysis of tear secretion amounts in a control group and an experimental group. The results show that: the rabbit lachrymal canal retained significantly more tears than the control group in which the punctum occlusion material prepared in example 1 was used as an embolic support.

FIG. 5 is a photograph of a stained section of corneal tissue of the control group and the experimental group. The results show that: the mucosa layer of the tissue section of the rabbit in the control group is proliferated and the surface layer is peeled, while the tissue section of the rabbit in the experimental group is obviously protected, and the lacrimal passage is healthy.

The above-mentioned embodiments only express the specific effects of the present invention, and the description thereof is not specific and detailed, and the dosage needs to be clinically adjusted by an ophthalmologist, and therefore, the scope of the present invention should not be construed as being limited thereby. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.

Claims (10)

1. A lacrimal canaliculus occlusion core material for use in a lacrimal canaliculus embolization procedure, wherein the lacrimal canaliculus occlusion core material is injectable in a liquid state below a critical temperature and in a gelled state above the critical temperature.

2. The lacrimal canaliculus obstruction material for lacrimal duct embolization according to claim 1, which is prepared from the following raw materials: 0.001-5% (w/v) hyaluronic acid, 12-30% (w/v) temperature-sensitive polymer, 5-45% (w/v) degradable polymer and the balance phosphate buffer solution.

3. The lacrimal canaliculus obstruction material for lacrimal duct embolization according to claim 2, wherein the molecular weight of the hyaluronic acid is 1000-15000 KDa.

4. The lacrimal canaliculus occlusion core material for lacrimal canaliculus embolization surgery according to claim 2, wherein the temperature sensitive polymer is one or more of a copolymer of polyoxyethylene and polyoxypropylene, pluronic F38, pluronic F68, pluronic F77, pluronic F87, pluronic F88, pluronic F127, polyisopropylacrylamide, gelatin and chitin.

5. The lacrimal canaliculus obstruction material for lacrimal embolization according to claim 2, wherein the degradable polymer is one or more of poly-L-lactic acid, poly-dl-lactic acid, poly-glutamic acid, polycaprolactone, and polycaprolactone polyol.

6. The lacrimal canaliculus obstruction core material for lacrimal duct embolization according to claim 1, wherein the concentration of the hyaluronic acid in the lacrimal canaliculus obstruction core material is 0.01-2% (w/v), the concentration of the thermo-sensitive polymer in the lacrimal canaliculus obstruction core material is 12-20% (w/v), and the concentration of the degradable polymer in the lacrimal canaliculus obstruction core material is 5-20% (w/v).

7. The lacrimal canaliculus occlusion material for lacrimal embolization according to claim 2, wherein the lacrimal canaliculus occlusion material further comprises a pharmaceutical and/or nutritional factor.

8. The method for preparing the lacrimal duct obstruction core material for the lacrimal duct embolism operation according to any one of claims 1 to 7, is characterized by comprising the following steps:

s1: dissolving hyaluronic acid powder in phosphate buffer solution;

s2: dissolving temperature-sensitive polymer powder in phosphate buffer solution;

s3: dissolving temperature-sensitive polymer powder in phosphate buffer solution;

s4: mixing the solutions in the S1-S3 at 0-12 ℃, and standing for 12-36 hours to obtain a lacrimal canaliculus obstruction core material;

wherein the concentration of the hyaluronic acid in the lacrimal canaliculus obstruction core material is 0.001-5% (w/v), the concentration of the thermo-sensitive polymer in the lacrimal canaliculus obstruction core material is 12-30% (w/v), and the concentration of the degradable polymer in the lacrimal canaliculus obstruction core material is 5-45% (w/v).

9. The method of claim 8, wherein the solution in the steps S1-S3 is dissolved in a vortex manner at 500-2000 rpm by using a mini-vibrator or a magnetic stirrer.

10. The method for preparing the lacrimal duct obstruction core material for the lacrimal duct embolism operation according to the claim 8, wherein the concentration of the hyaluronic acid in the lacrimal duct obstruction core material is 0.01-2% (w/v), the concentration of the thermo-sensitive polymer in the lacrimal duct obstruction core material is 12-20% (w/v), and the concentration of the degradable polymer in the lacrimal duct obstruction core material is 5-20% (w/v).

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