CN115501175A - Biodegradable hydrogel composition for delivery of multiple drugs and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the field of drug delivery carriers, and particularly relates to a biodegradable hydrogel composition for delivery of multiple drugs, and a preparation method and application thereof. More particularly, the present invention relates to a biodegradable hydrogel composition for blocking or reducing tear flow through a punctum or canaliculus of a human eye and delivering a plurality of drugs to the eye, comprising a drug uniformly dispersed within the hydrogel and providing sustained release administration of the drug to a tear film of a user over a predetermined period of time. The hydrogel composition comprises a drug that will gradually dissolve in the tear fluid and be released to the eye continuously, and a polymer network comprising two different polyethylene glycol (PEG) units: a first PEG unit for adjusting an internal pore size and a degree of cross-linking of the polymer network, and a second PEG unit constituting a main body of the polymer network.

Description

Biodegradable hydrogel composition for delivery of multiple drugs and preparation method and application thereof

Technical Field

The invention belongs to the field of drug delivery carriers, and particularly relates to a biodegradable hydrogel composition for delivery of multiple drugs, and a preparation method and application thereof.

Background

Drug delivery to the eye is often accomplished by periodic administration of eye drops, pastes and bandages (proteins-and-bandages), administration of drug-loaded corneal lenses, direct injection, or drug depots placed into the eye. For example, antibiotics need to be administered every few hours for several days after cataract and vitreoretinal surgery. In addition, frequent administration of other drugs, such as non-steroidal anti-inflammatory drugs (NSAIDS), may be required. In general, ophthalmic agents for treating diseases or conditions of the eye are directed to treating surface conditions of the eye, anterior segment diseases of the eye, or posterior segment diseases of the eye.

Most drugs delivered to the surface and front of the eye are administered in the form of eye drops. This delivery format suffers from several problems: first, for elderly patients with arthritis, it may be difficult to get eye drops into the eye. Second, it is estimated that up to 95% of the drug in eye drops does not eventually penetrate into the eye and is wasted. This not only results in inefficient drug utilization, but can also result in systemic side effects (e.g., beta blockers for glaucoma can lead to cardiovascular problems). Finally, to be able to achieve the desired therapeutic concentration, designers have to administer greater concentrations of drugs, which can lead to local problems such as burns and punctures or ocular surface discomfort, resulting in poor patient compliance. However, to date, eye drops remain the primary means of ophthalmic drug delivery.

A variety of drug reservoirs have been produced for delivering ophthalmic drugs. Delivery of consistent doses of drugs over time has become a major problem throughout the drug delivery industry in the united states since the first large-scale commercialization of drug delivery technology in the fifties of the twentieth century. The main solution is a reservoir implant (degradable or non-degradable) within the vitreous. These implants have very small dimensions and high drug concentrations. Despite their smallness, they still require administration with needles of 22-25G size, or surgical implantation or removal when needed. For example, adipamide (Ozurdex (elan)) is a biodegradable vitreous implant for macular edema disorders in adult patients caused by Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO), delivered into the vitreous cavity using a 22G delivery system. As another example, susvimo (roche), previously known as a Ranibizumab Port Delivery System (PDS) with Ranibizumab, is a permanent, refillable intraocular implant of about one meter in size that is surgically implanted into the vitreous and can be continuously filled (once in 6 months) for sustained Delivery of custom formulated Ranibizumab (Ranibizumab) over several months. Both needle injection and surgical implantation can cause trauma and pain, and are prone to various adverse reactions such as endophthalmitis, which can seriously affect patient compliance.

Based on the above, other approaches to ocular drug delivery have been developed. Punctal plugs were originally a medical prosthesis for the relief of dry eye by partially occluding the tear drainage canals to increase the natural tear on the ocular surface for lubrication. Later punctal plugs were designed to load sustained release reservoirs of drug because of their superior characteristics of non-invasive placement removal, ease of handling and positioning, direct sustained release of drug to the tear film, and the like. For example, as disclosed in U.S. patent No. 2008/0038317, punctal plugs are made with an internal reservoir and some biodegradable polymer that further has an impermeable membrane or other special release controller to control the rate of drug release in the plug. As another example, U.S. patent No. 6196993 discloses a punctal plug with an internal drug loading reservoir that can have an aperture sized and shaped to release the drug in the reservoir at a useful rate.

Despite these advances, conventional drug-loaded punctal plugs, due to their single composition, require separate design of the plug components and amounts for each drug-loaded punctal plug, and additional drug carriers such as microspheres when the drug is poorly water soluble, which increases the time, difficulty and cost of development and manufacture. In addition, different drugs require different sustained release times, and the traditional drug-loaded punctal plugs have difficulty in controlling the sustained release speed of the drugs at low cost. As described above, traditional drug-loaded punctal plugs appear to be too distracting to address the myriad of drug species and treatment cycles that vary from person to person. Clinically, there is a need for a more stable, more efficient, and more economical platform for ocular drug delivery vehicles to achieve better ocular disease management. Chinese patent CN 102395401B discloses a hydrogel lacrimal canaliculus plug formed by crosslinking a single PEG derivative as a precursor, which comprises microspheres encapsulating a drug and dispersed in the hydrogel, and can provide a sustained release time of the drug of about 30 days. The patent is characterized in that the precursor component is single, the inner pore size and the slow release time of the hydrogel are fixed, the design from the head is needed if the specification of the drug is changed or other drugs are loaded, and the slow release time is difficult to adjust. On the other hand, the production process of the microsphere for encapsulating the drug is complex and the quality is verified fussy, so that the economic cost and the time cost for drug research and development are greatly improved.

In view of the above, there is an urgent need to develop a biodegradable ophthalmic hydrogel composition which has strong controllability, wide drug loading application range, simple preparation method and low cost and can be used for delivering various drugs.

Disclosure of Invention

In order to solve the above technical problems, the present invention provides a novel biodegradable hydrogel composition for multi-drug delivery, a preparation method thereof and use thereof. Particularly, the invention provides a novel hydrogel lacrimal duct inner plug for slow release of various ophthalmic drugs, and the proportion of each component of the hydrogel and the particle size of micronized drug particles can be adjusted according to the water solubility, the action position, the slow release time and the like of the drugs to meet different requirements.

Specifically, the invention is realized by the following technical schemes:

in a first aspect, the present invention provides an ophthalmic hydrogel composition with controlled biodegradation time, the hydrogel composition comprising a drug which will gradually dissolve in tear fluid and be released to the eye continuously, and a polymer network comprising 2 different polyethylene glycol (PEG) units: a first PEG unit for adjusting an internal pore size and a degree of cross-linking of the polymer network, and a second PEG unit constituting a main body of the polymer network.

Alternatively, in the above hydrogel composition, wherein the first PEG unit comprises a plurality of multi-arm PEG units having 2 to 10 arms.

Preferably, the first PEG unit comprises a plurality of multi-arm PEG units having 2 to 8 arms.

Preferably, the first PEG unit comprises a plurality of multi-arm PEG units having 2 to 6 arms.

Preferably, the first PEG unit comprises a plurality of multi-arm PEG units having 2 to 4 arms.

Preferably, the first PEG unit comprises a plurality of multi-arm PEG units having 2 arms.

And/or, wherein the second PEG unit comprises a plurality of multi-arm PEG units having 4 to 10 arms.

Preferably, the second PEG unit comprises a plurality of multi-arm PEG units having 4 to 8 arms.

Preferably, the second PEG unit comprises a plurality of multi-arm PEG units having 2 to 6 arms.

Preferably, the second PEG unit comprises a plurality of multi-arm PEG units having 6 arms.

Preferably, the second PEG unit comprises a plurality of multi-arm PEG units having 4 arms.

Alternatively, in the hydrogel composition, a molar ratio of the first PEG unit to the second PEG unit is between 0 and 5.

Preferably, the molar ratio of the first PEG unit to the second PEG unit is between 0 and 3.

Preferably, the molar ratio of the first PEG unit to the second PEG unit is between 0 and 1.

Alternatively, in the above hydrogel composition, wherein the polymer network is formed by reacting a plurality of PEG units with one or more PEG or ornithine based amine groups.

Preferably, the first PEG unit is selected from sazegsaz (20K), SAPPEGSAP (20K), SGPEGSG (20K) or SSPEGSS (20K), the second PEG unit is selected from 4a20KPEGSAZ, 4a20kpeg SAP, 4a20KPEGSG, 4a20KPEGSS, 8a20KPEGSAZ, 8a20KPEGSAP, 8a20KPEGSG or 8a20KPEGSS, and the PEG or ornithine-based amine group is selected from NH2PEGNH2 (20K), 4a20KPEGNH2, 8a20KPEGNH2 or polyornithine or a salt thereof.

More preferably, the polymer network host is formed by reacting SGPEGSG (20K) and 4a20KPEGSG with trionithine or a salt thereof.

Alternatively, in the above hydrogel composition, wherein the polymer network is amorphous under aqueous conditions, or wherein the polymer network is semi-crystalline in the absence of water.

Alternatively, in the above hydrogel composition, wherein the polymer network further comprises a color developer, the color developer is effective to provide visibility of the hydrogel composition to the naked human eye.

Preferably, the colour developer is selected from one or more of: FD & C BLUE No.1, eosin, methylene BLUE, indocyanine green, N-hydroxysuccinimide fluorescein (NHS-fluorescein), fluorescein, or colored dyes commonly found on synthetic surgical sutures.

Preferably wherein the colour developer is chemically modified to facilitate attachment to the polymer network.

Preferably wherein the colour developer is chemically linked to the polymer network.

More preferably, wherein the chromogenic agent is N-hydroxysuccinimide fluorescein (NHS-fluorescein).

Alternatively, in the hydrogel composition, the polymer network further comprises a buffer medium for adjusting pH.

Preferably, the buffering medium for adjusting the pH is selected from one or more of the following: potassium dihydrogen phosphate-sodium hydroxide buffer pair, sodium dihydrogen phosphate-citric acid buffer pair, sodium dihydrogen phosphate-disodium hydrogen phosphate buffer pair, 4-hydroxyethylpiperazine ethanesulfonic acid-disodium hydrogen phosphate buffer pair, or triethanolamine-hydrochloric acid buffer pair.

More preferably, wherein the buffer medium is a sodium dihydrogen phosphate-disodium hydrogen phosphate buffer pair.

Alternatively, in the above hydrogel composition, wherein the drug is uniformly dispersed within the polymer network.

Preferably, wherein the drug is delivered to the eye continuously over a period of about 12 hours to 90 days.

More preferably, the drug is delivered to the eye continuously over a period of about 1 to 80 days.

Still more preferably, the drug is delivered to the eye continuously over a period of about 2 to 60 days.

Alternatively, in the above hydrogel composition, wherein the drug is micronized.

Preferably, the micronized particle size range of the drug substance is D ₉₇ ＝2-50μm。

More preferably, the micronized particle size range of the drug substance is D ₉₇ ＝2-30μm。

Still more preferably, the micronized particle size range of the drug substance is D ₉₇ ＝2-15μm。

Alternatively, in the above hydrogel composition, wherein the hydrogel composition spontaneously degrades by chemical hydrolysis in water; or, wherein the hydrogel composition does not degrade until the drug is completely released; or, wherein the hydrogel composition is discharged after natural degradation or removed manually.

Preferably, the hydrogel is an intraluminal lacrimal plug.

As an exemplary embodiment, in the hydrogel composition, wherein the drug is dexamethasone.

Preferably, the dexamethasone is slowly released from the hydrogel placed in the lacrimal canaliculus to the lacrimal film within a period of at least 4 weeks to effectively relieve symptoms of conjunctival congestion, ocular pruritus, lacrimation, etc., of patients with allergic conjunctivitis.

As another exemplary embodiment, in the hydrogel composition, the drug is brimonidine tartrate.

Preferably, the brimonidine tartrate is slowly released from a hydrogel placed in the lacrimal canaliculus to the tear film over a period of at least 2 weeks to effectively reduce intraocular pressure in patients with open angle glaucoma and ocular hypertension.

In a second aspect, the present invention provides the use of a hydrogel composition as described in the first aspect above for the preparation of an ophthalmic medicament.

In a third aspect, the present invention provides a method for producing the hydrogel composition according to the first aspect.

It is contemplated by those skilled in the art that the hydrogel composition of the first aspect described above may be prepared by any method known in the art.

Alternatively, in one non-limiting example, the representative preparation method comprises the steps of:

(1) Dissolving 4a20KPEGSG and SGPEGSG (20K) in phosphate buffer;

(2) Dissolving trionithine in phosphate buffer;

(3) Suspending the micronized drug in phosphate buffer;

(4) Mixing all the liquids, adding NHS-fluorescein, and mixing again;

(5) Rapidly sucking the mixed liquid into a thin tube having a known diameter;

(6) Closing the port with a clamp and keeping the port vertical until the crosslinking reaction is complete;

(7) Remove the clamp and stretch the gel/tube to 2.5 times its original length, dry for 48 hours at 30 ℃;

(8) The dried plug in the tube was removed and cut to a length of 3.5-4.5 mm.

Alternatively, the phosphate buffer is at a molarity of 0.1M.

Optionally, the mass fraction of the 4a20KPEGSG in the dry plug ranges from 30% to 80%.

Preferably, the mass fraction of the 4a20KPEGSG in the drying plug ranges from 40% to 70%.

Alternatively, the SGPEGSG (20K) may have a mass fraction in the range of 0 to 50% in the dry plug.

Preferably, the mass fraction of the SGPEGSG (20K) in the dry plug ranges from 0% to 35%.

Optionally, the mass fraction of the trionithine in the dry plug ranges from 0.5% to 25%.

Preferably, the mass fraction of said trionithine in said dry plug ranges from 1% to 15%.

As an alternative mode, according to the characteristics and sustained release requirements of different drugs, the loading amount of the drug in the drying plug can be flexibly adjusted, and the mass fraction range of the drug is 5% -60%.

Alternatively, the content of NHS-fluorescein is expressed as weight/volume after the dry plug is saturated with reabsorbed water, and the NHS-fluorescein is less than 1% weight/volume.

Preferably, the NHS-fluorescein is less than 0.01% weight/volume.

More preferably, the NHS-fluorescein is less than 0.001% weight/volume.

Alternatively, the tubule has a diameter of less than 1 mm.

Preferably, the tubules have a diameter of less than 0.7 mm.

Compared with the prior art, the invention has the following beneficial effects:

unlike the exemplary prior art cited in the background of the invention section, the hydrogel lacrimal canaliculus plug of the invention is formed by covalent crosslinking of two different PEG derivatives as precursors and polyornithine as a crosslinking agent, and the drug is dispersed in the hydrogel after micronization. The benefits of this are:

first, the ratio of the two PEG derivative precursors of the hydrogel and the micronized particle size of the drug can be adjusted according to the treatment course of the specific drug to meet the specification and sustained release requirements of the specific drug. The hydrogel lacrimal canaliculus inner plug loaded with dexamethasone and used for treating allergic conjunctivitis is prepared by the method, and three specifications of hydrogel lacrimal canaliculus inner plugs with 10 percent, 20 percent and 40 percent drug loading can be obtained by adjusting the proportion of two PEG derivative precursors, the micronized particle size of the loaded dexamethasone and the loading amount, and the hydrogel lacrimal canaliculus inner plug respectively has the slow release time of about 14 days, about 30 days and about 60 days. Compared with the fixed drug loading and slow release time of the hydrogel lacrimal canaliculus inner plug disclosed in the Chinese patent CN 102395401B, the method disclosed by the invention is economic and rapid, different specifications and different slow release times of the hydrogel lacrimal canaliculus inner plug of a specific drug are realized with lower cost and shorter time, a complex microsphere process is avoided, the specific requirements of different patients can be met, and the compliance of the patients is improved.

Secondly, the proportion of two PEG derivative precursors of the hydrogel and the particle size of drug micronization can be adjusted according to the physicochemical properties of different drugs, so as to meet the loading amount and the slow release requirements of different drugs in the hydrogel lacrimal canaliculus plug. As described above, for dexamethasone loading, adjusting the ratio of the two PEG derivative precursors of the hydrogel and the micronized particle size of the drug can yield hydrogel punctum plugs of three sizes with different sustained release times. For other drugs, such as brimonidine tartrate, the ratio of the two PEG derivative precursors and the micronized particle size of the drug were determined based on their physicochemical properties, resulting in a hydrogel punctal plug loaded with 20% brimonidine tartrate, with a sustained release time of about 14 days. Different drugs have different physicochemical properties, and the corresponding hydrogel pore sizes are different in order to meet the loading and slow release requirements. The pore size of the drug-loaded hydrogel determines the loading capacity and the sustained release rate of the drug, and needs to be matched with the physicochemical properties of the drug and the particle size of the drug particles. The lacrimal canaliculus plug disclosed in chinese patent CN 102395401B is a hydrogel with a single precursor, and the inner pore size of the hydrogel is fixed, although the inner pore size of the hydrogel can be changed by adjusting the ratio of the precursor and the cross-linking agent, i.e. changing the degree of cross-linking, but at the cost of changing the overall physical properties of the hydrogel, such as elastic modulus, toughness, etc. These characteristics are important for an intraductal punctal plug, as it is stably placed in the lacrimal canaliculus or it is not deformed and slipped out by an uncontrollable external force (e.g., rubbing the eye). The method flexibly controls the size of the inner pore diameter of the hydrogel by adjusting the proportion of the two PEG derivative precursors, does not change the crosslinking degree, determines the particle size of the micronized drug particles according to the physical and chemical properties of the specific drug, meets the loading and slow release requirements of various drugs on the hydrogel lacrimal canaliculus inner plug, is convenient and rapid, and saves the cost.

Drawings

FIG. 1:4a chemical structure of 20 KPEGSG.

FIG. 2: chemical structure of SGPEGSG.

FIG. 3: chemical structure of trionithine.

FIG. 4: hydrogel lacrimal intratubular plug in vitro dissolution profiles loaded with 10%, 20%, and 40% dexamethasone.

FIG. 5: the median concentration of dexamethasone for each specification in the tear fluid of beagle varied with time.

Detailed Description

The invention mainly aims to provide a hydrogel lacrimal canaliculus inner plug for slow release of various ophthalmic medicines, which can adjust the proportion of each component of the hydrogel and the particle size of micronized medicine particles according to the water solubility, the action position, the slow release time and the like of the medicines so as to meet different requirements.

As used herein, a "hydrogel" is defined as a 3D polymer network in which an aqueous solution is present as a solvent. Most hydrogels consist of 90% water. Hydrogels are often formed by cross-linking water-soluble molecules to form an essentially infinite molecular weight network. Hydrogels with high water content are generally flexible materials. When made of a flexible material, the hydrogel having a high water content is comfortable to wear in the eye without a foreign body sensation. The disclosed intraluminal plug is a covalently crosslinked hydrophilic polymer (absorbs water to form a biodegradable hydrogel) that contacts and absorbs water to swell in situ to enlarge the lacrimal canaliculus for secure and stable installation in the lacrimal canaliculus. The intra-lacrimal plug is elastic and extends deeper into the lacrimal canaliculus than the punctal plug (which is placed on top of the lacrimal punctum), and does not fall or deform when the patient rubs the eye or the hydrogel is otherwise stretched or squeezed.

In practice, to achieve this, the punctal plugs should be dry and contain little water (trace amounts of water) when used. When placed in the lacrimal canaliculus of a user, the dry plug absorbs tears, expands rapidly in a radial direction until it is caught against the inner wall of the lacrimal canaliculus to fit securely in the lacrimal canaliculus, and contracts slightly in an axial direction so that the plug retracts into the lacrimal canaliculus. Molecular orientation provides a mechanism for anisotropic expansion upon introduction into a hydration medium: the material is stretched and then allowed to cure, locking the molecular orientation to give it an angle. This may be achieved by imbibing the material while heating to a temperature above the melting point of the crystallizable region of the material, and then allowing the crystallizable region to crystallize. Alternatively, the glass transition temperature of the dried hydrogel can be used to lock in molecular orientation. Alternatively, the gel is stretched before being completely dehydrated (or dried) and then the material is dried under tension.

The hydrogel is formed from a reaction of precursors. The precursors are not hydrogels but are covalently cross-linked to each other to form a hydrogel and are thus part of a hydrogel. The crosslinks may be formed by covalent or ionic bonds, by hydrophobic associations of precursor molecular segments, by crystallization of precursor molecular segments, and the like. Among other things, covalent cross-linking often provides stability and predictability of reactant product architectures. The precursors may be polymerizable and include a crosslinking agent (which is often, but not always, a polymerizable precursor) that reacts upon contact with each other to form a crosslinked hydrogel. The polymerizable precursor is thus a precursor having the following functional groups: the functional groups react with each other to form a polymer made of repeating units.

As used herein, "polyethylene glycol (PEG)" is a water-soluble polyether-type high molecular compound widely used in the fields of medicine, hygiene, food, chemical industry, and the like. PEG has many advantages such as low toxicity, non-thrombogenic properties, biocompatibility, and ability to be rapidly excreted by the body without any toxic side effects. The hydrogel composition of the invention selects two different end-modified multi-arm PEGs as precursors, wherein the first precursor is selected from SAZPEGSSAZ (20K), SAPPEGSAP (20K), SGPEGSG (20K), SSPEGSS (20K), preferably SGPEGSG (20K); the second precursor is selected from the group consisting of 4a20K PEG SAZ, 4a20K PEG SAP, 4a20K PEG SG, 4a20K PEG SS, 8a20K PEG SAZ, 8a20K PEG SAP, 8a20K PEG SG, and 8a20K PEG SS, preferably 4a20K PEG SG. The use of two different precursors has the advantage that when the ratio of the two precursors is changed, the size of the internal pore size of the hydrogel is changed, and the size of the internal pore size determines the particle size and dissolution rate of the drug dispersed in the hydrogel. The molar ratio of the first precursor to the second precursor is selected from 0 to 5, preferably 0 to 3, more preferably 0 to 1. The chemical structural formula of 4a20KPEGSG is shown in figure 1, and the chemical structural formula of SG PEG SG is shown in figure 2.

The two PEG precursors described above are reacted with one or more PEG or ornithine based amine groups selected from the group consisting of NH2PEG NH2 (20K), 4a20K PEG NH2, 8a20K PEG NH2, and polyornithine or a salt thereof, preferably trionithine, to form a hydrogel. The molecular weight of the trionithine as a cross-linking agent is small compared to that of the PEG precursor, and theoretically the optimal molar ratio of the free amino groups of the trionithine to the total terminal N-hydroxysuccinimide groups of the PEG precursor should be 1:1, however, in practical applications, the molar ratio is selected from 8:1 to 2:1, preferably 4:1 to 2:1, in order to obtain a hydrogel having a desired physical strength and flexibility. The chemical structure of trionithine is shown in FIG. 3.

Many drugs, especially the newly developed substances, are poorly water soluble, which limits their bioavailability. The use of micronized drug may improve solubility, and drug powders containing micron-sized drug particles may be used in a variety of pharmaceutical dosage forms. The hydrogel composition disclosed by the invention has micronized drugs, so that the drug with low solubility in water, such as dexamethasone, can be uniformly dispersed in the hydrogel without a cosolvent and can be stably and slowly released to the tear film. The preferred micronized particle size range is D ₉₇ =2-50 μm, more preferred micronised particle size range D ₉₇ =2-30 μm, the most preferred micronized particle size range is D ₉₇ ＝2-15μm。

In the case of an intra-lacrimal plug, without being bound to a particular theory, it is hypothesized that physiological fluid accumulates at the morphological top of the plug and provides a liquid column, which causes drug release to be limited by the cross-sectional area of the proximal portion of the plug. The inner wall of the lacrimal canaliculus appears to elute the drug at a much slower rate relative to the depletion of the drug through the liquid column. Alternatively, or in addition, the canalicular wall may be saturated with the drug, so that release through the wall is slowed, and the egress of the drug is transferred to the end of the plug. As described above, the time for the sustained release of the drug is greatly prolonged.

Controlled release is a complex area where the drug needs to reach a minimum threshold concentration to ensure efficacy, while too high a concentration can cause adverse reactions and side effects. In general, a zero order release profile is desirable: the release was constant over time, with the rate being independent of changes in reactant concentration. However, hydrogel materials are hydrophilic and allow aqueous solutions (tears) to permeate through and pass through, and the diffusion process of the drug is concentration dependent. On the other hand, in the case of degradable materials, the situation is more complicated if the degradation affects the drug release rate. Disclosed herein are hydrogel compositions having a substantially zero order rate of drug release over a predetermined period of time.

The hydrogel composition of the present invention contains a color-developing agent which is effective in providing visibility of the hydrogel composition to the naked human eye. The lacrimal punctum plug can shift as the hydrogel degrades, in which case a comfortably placed lacrimal punctum plug can shift unnoticed by the patient. Incorporating the visualization agent at the appropriate concentration allows the user to monitor the immediate presence of the plug in the lacrimal canaliculus and take action to effect repositioning before the treatment regimen is completed. The color developing agent reflects or emits light with a wavelength detectable by human eyes, so that a user can conveniently observe the plug in the lacrimal canaliculus.

The visualization agent may be selected from any of a variety of non-toxic colored substances suitable for use in medical implantable medical devices, such as FD & C BLUE No.1, eosin, methylene BLUE, indocyanine green, N-hydroxysuccinimide fluorescein (NHS-fluorescein), fluorescein, or colored dyes commonly found in synthetic surgical sutures. The developer may be present with a reactive precursor material, such as a cross-linking agent or a solution of a functional polymer. Preferred colored substances may or may not be chemically attached to the hydrogel. The developer may generally be used in small amounts, preferably less than 1% weight/volume, more preferably less than 0.01% weight/volume, and most preferably less than 0.001% weight/volume.

As a representative example, the disclosed intraductal plugs effectively deliver a therapeutic amount of dexamethasone to male beagle dogs over the course of about 4 weeks, as shown in fig. 4, with the concentration of dexamethasone in the tear fluid gradually decreasing over the 4 week period. At each time point, the results of ophthalmic examinations of all eyes were not considered adverse and no ocular toxicity was observed.

As a representative example, the disclosed intraluminal lacrimal plugs effectively deliver a therapeutic amount of brimonidine tartrate to male beagle dogs over the course of about 2 weeks, with the concentration of brimonidine tartrate in the tear fluid gradually decreasing over the 2 week period. At each time point, the results of the ophthalmic examination of all eyes were not considered adverse and no ocular toxicity was observed.

The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are illustrative only and are not limiting upon the scope of the invention.

The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not indicated by manufacturers and are available from normal sources.

The experimental procedures in the following examples are all conventional ones unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.

Preparation examples:

example 1: preparation of hydrogel lacrimal canalicular plug with 10% loading of dexamethasone by weight

As shown in table 1, the material composition comprises the following raw materials by mass percent:

table 1: 10% loading of hydrogel lacrimal punctum plug composition of dexamethasone wt%

Components	Quality (g)
		4a20K PEG SG	1.268
SGPEGSG(20K)	0.576
		Triornithine	0.090
Dexamethasone	0.232
		NHS-fluorescein	0.013
Sodium dihydrogen phosphate	0.038
		Disodium hydrogen phosphate	0.101
Water for injection	15.580

The preparation method comprises the following steps:

1. a phosphate buffer was prepared from 0.038g of sodium dihydrogenphosphate, 0.101g of disodium hydrogenphosphate, and 15.58g of water for injection.

2. Micronizing (D) ₉₇ =5 μm) of dexamethasone was suspended in 8.22g of phosphate buffer。

3. 0.09g of trionithine was dissolved in 1.41g of phosphate buffer.

4. 1.268g of 4a20K PEG SG and 0.576g of SGPEGSG (20K) were dissolved in 6.089g of phosphate buffer.

5. The prepared solution of 2-4 was mixed and 0.013g NHS-fluorescein was added and mixed well.

6. The solution was aspirated into a thin tube of known diameter, the port was closed with a clamp and held vertical until the crosslinking reaction was complete.

7. The clip was removed and the gel/tube stretched to 2.5 times its original length. Dried at 30 ℃ for 48 hours.

8. The dried plug in the tube was removed and cut to a length of 3.5-4.5 mm.

Through detection, the pH value of the mixed solution before crosslinking is 7.0; drying and cutting to obtain finished medicine-carrying lacrimal canaliculus inner plugs with uniform sizes; sustained release was provided in the lacrimal canaliculus of beagle dogs for about 30 days, and no ocular toxicity was observed.

Example 2: preparation of hydrogel lacrimal canalicular plug loaded with 20% by weight dexamethasone

As shown in table 2, the material composition comprises the following raw materials by mass percent:

table 2: hydrogel lacrimal canalicular plug composition loaded with 20% wt dexamethasone

Components	Quality (g)
		4a20K PEG SG	1.195
SGPEGSG(20K)	0.314
		Triornithine	0.090
Dexamethasone	0.428
		NHS-fluorescein	0.013
Sodium dihydrogen phosphate	0.038
		Disodium hydrogen phosphate	0.101
Water for injection	15.580

The preparation method comprises the following steps:

1. a phosphate buffer was prepared from 0.038g of sodium dihydrogenphosphate, 0.101g of disodium hydrogenphosphate, and 15.58g of water for injection.

2. Micronizing (D) ₉₇ =5 μm) of 0.428g dexamethasone was suspended in 8.22g phosphate buffer.

3. 0.09g of trionithine was dissolved in 1.41g of phosphate buffer.

4. 1.195g of 4a20K PEG SG and 0.314g of SGPEGSG (20K) were dissolved in 6.089g of phosphate buffer.

5. The prepared solution of 2-4 was mixed and 0.013g NHS-fluorescein was added and mixed well.

6. The solution was drawn into a thin tube of known diameter, the port was closed with a clamp and held vertical until the crosslinking reaction was complete.

7. The clip was removed and the gel/tube stretched to 2.5 times its original length. Dried at 30 ℃ for 48 hours.

8. The dried plug in the tube was removed and cut to a length of 3.5-4.5 mm.

Through detection, the pH value of the mixed solution before crosslinking is 7.1; drying and cutting to obtain finished medicine-carrying lacrimal canaliculus inner plugs with uniform sizes; sustained release was provided in the lacrimal canaliculus of beagle dogs for about 30 days, and no ocular toxicity was observed.

Example 3: preparation of hydrogel lacrimal canalicular plug loaded 40% wt dexamethasone

As shown in table 3, the composition comprises the following raw materials in percentage by mass:

table 3: hydrogel lacrimal canalicular plug composition loaded with 40% wt dexamethasone

Components	Quality (g)
		4a20K PEG SG	1.930
SGPEGSG(20K)	0
		Triornithine	0.120
Dexamethasone	1.468
		NHS-fluorescein	0.013
Sodium dihydrogen phosphate	0.038
		Disodium hydrogen phosphate	0.101
Water for injection	13.960

The preparation method comprises the following steps:

1. a phosphate buffer was prepared from 0.038g of sodium dihydrogenphosphate, 0.101g of disodium hydrogenphosphate, and 15.58g of water for injection.

2. Micronizing (D) ₉₇ =15 μm) of 1.468g dexamethasone was suspended in 8.01g phosphate buffer.

3. 0.12g of trionithine was dissolved in 0.6g of phosphate buffer.

4. 1.930g of 4a20K PEG SG was dissolved in 5.489g of phosphate buffer.

5. The prepared solution of 2-4 was mixed and 0.013g NHS-fluorescein was added and mixed well.

6. The solution was drawn into a thin tube of known diameter, the port was closed with a clamp and held vertical until the crosslinking reaction was complete.

7. The clip was removed and the gel/tube stretched to 2.5 times its original length. Dried at 30 ℃ for 48 hours.

8. The dried plug in the tube was removed and cut to a length of 3.5-4.5 mm.

Through detection, the pH value of the mixed solution before crosslinking is 7.1; drying and cutting to obtain finished medicine-carrying lacrimal canaliculus inner plugs with uniform sizes; sustained release was provided in the lacrimal canaliculus of beagle dogs for about 60 days, and no ocular toxicity was observed.

Example 4: preparation of hydrogel intrapunctal plugs loaded with 15% by weight of brimonidine tartrate

As shown in table 4, the composition comprises the following raw materials by mass percent:

table 4: 15% loading of a hydrogel punctal plug of brimonidine tartrate

Components	Quality (g)
		4a20K PEG SG	1.224
SGPEGSG(20K)	0.044
		Triornithine	0.083
Brimonidine tartrate	0.265
		NHS-fluorescein	0.013
Sodium dihydrogen phosphate	0.038
		Disodium hydrogen phosphate	0.101
Water for injection	15.580

The preparation method comprises the following steps:

1. phosphate buffer was prepared with 0.038g of sodium dihydrogenphosphate, 0.101g of disodium hydrogenphosphate and 15.58g of water for injection.

2. Micronizing (D) ₉₇ =7 μm) of 1.05g brimonidine tartrate is suspended in 8.22g phosphate buffer.

3. 0.083g of trionithine is dissolved in 1.41g of phosphate buffer.

4. 1.224g of 4a20K PEG SG and 0.044g of SGPEGSG (20K) were dissolved in 6.089g of phosphate buffer.

5. The prepared solution of 2-4 was mixed and 0.013g NHS-fluorescein was added and mixed well.

6. The solution was drawn into a thin tube of known diameter, the port was closed with a clamp and held vertical until the crosslinking reaction was complete.

7. The clip was removed and the gel/tube stretched to 2.5 times its original length. Dried at 30 ℃ for 48 hours.

8. The dried plug in the tube was removed and cut to a length of 3.5-4.5 mm.

Through detection, the pH value of the mixed solution before crosslinking is 6.8; drying and cutting to obtain finished medicine-carrying lacrimal canaliculus inner plugs with uniform sizes; sustained release was provided in the lacrimal canaliculus of beagle dogs for about 14 days, and no ocular toxicity was observed.

Effect embodiment:

experimental example 1: in vitro release assay for dexamethasone-loaded hydrogel punctum inner plug

Hydrogel punctal plugs loaded with 10%, 20% and 40% dexamethasone were prepared as described in examples 1-3 of the invention. The hydrogel composition can realize the controlled slow release of the drug, and the in-vitro slow release time of the two hydrogel lacrimal canaliculus inner plugs loaded with different mass fractions of dexamethasone is determined through an in-vitro release experiment.

High performance liquid chromatography (general rule 0512) is selected to determine the content of dexamethasone according to 2020 edition of Chinese pharmacopoeia. Precisely weighing a sample, adding methanol for dissolving, quantitatively diluting to obtain a solution containing about 50 μ g of the sample per 1mL, precisely weighing 20 μ L of the sample, injecting into a liquid chromatograph, and recording chromatogram; and measuring dexamethasone as reference substance by the same method. And calculating by peak area according to an external standard method to obtain the content of dexamethasone in the sample. And (5) processing the data and then plotting to obtain a dissolution curve.

In a 125mL polypropylene bottle, 100mL of PBS with ph =4.0 was added. The drug loaded stopper was placed into a polypropylene bottle and the lid was closed, and the bottle was placed in a 37.0 + -0.3 deg.C water bath. The polypropylene bottles were left undisturbed in the water bath until sampling. At each sampling time point, the polypropylene vial was gently inverted and rotated to ensure uniform mixing, and 1.0mL of supernatant (1/3 sample down the vial) was removed and transferred to an HPLC vial and 1.0mL of heated PBS was added to the polypropylene vial and the cap was closed. The sampling time is 1, 2, 5, 10, 15, 20, 25, 30, 40, 50, 60 days. The in vitro dissolution profile of the dexamethasone-loaded hydrogel intraductal punctum plug is shown in figure 4.

The results show that the hydrogel lacrimal canaliculus plug with the three specifications slowly releases dexamethasone at a stable rate. As previously described, the in vitro release of the drug-loaded hydrogel lacrimal canaliculus inner plug is different from the in vivo release of the drug, and the diffusion of the drug is more rapid without being blocked by the inner wall of the lacrimal canaliculus, so that the sustained-release time in the lacrimal canaliculus is presumed to be longer.

Experimental example 2: pharmacokinetic study of dexamethasone-loaded hydrogel lacrimal canaliculus in beagle dogs

Hydrogel punctal plugs loaded with 10%, 20% and 40% dexamethasone were prepared as described in examples 1-3 of the invention. The beagle model was chosen because its eye and nasolacrimal system are anatomically similar to humans, and therefore the same clinical exposure pathway can be achieved; the objective was to determine the levels of dexamethasone in the tear fluid over time following insertion of the dexamethasone-loaded hydrogel punctal plugs into the dog canaliculi. Beagle dogs at least 6 months old and weighing 5 to 10 kg were used in the study, with 6 female beagle dogs loaded with 10% dexamethasone hydrogel intraductal plugs, for a total of 12 eyes participating in the experiment; 8 female beagle dogs are loaded with 20% dexamethasone hydrogel lacrimal canaliculus inner plugs, and 16 eyes are involved in the experiment; male beagle 12 were used to load a 40% dexamethasone hydrogel punctal plug, and a total of 24 eyes were involved in the experiment.

The punctal area was hydrated with a balanced salt solution after inserting the intra-lacrimal plug into the inferior lacrimal canaliculus of both eyes of the anesthetized beagle dog using forceps. For hydrogel punctal plugs loaded with 10% dexamethasone, 2 animals (4 eyes) were selected on days 0 (6 hours post insertion), 7, 14, respectively, for Tear collection, bilateral punctal plug removal, and ocular examination using Tear detection filter strips (Schirmer Tear Test strips), and the experiment was withdrawn; for hydrogel punctal plugs loaded with 20% dexamethasone, 2 animals (4 eyes) were selected on days 7, 14, 21 and 28, respectively, for tear collection, bilateral punctal plug removal and ophthalmic examination using tear detection filter paper strips, and the experiment was withdrawn; for the 40% dexamethasone-loaded hydrogel intraductal plug, 2 animals (4 eyes) were selected on days 0 (6 hours post insertion), 14, 28, 42, 56, and 60, respectively, for tear collection, bilateral intraductal plug removal, and ophthalmic examination using tear detection filter paper strips, and the experiment was withdrawn. 10% and 20% drug-loaded intraductal plugs the lacrimal area of each study eye was evaluated weekly to observe lacrimal punctum Guan Nasai (fluorescein-conjugated hydrogels allowed visualization using slit lamps with blue and yellow filters); for a 40% drug-loaded intraductal plug, the assessment was performed every two weeks. Ophthalmic examinations included anterior segment structural examinations (conjunctiva, cornea, iris, corneal pannus and lens) and posterior segment structural examinations (vitreous, optic disc/nerve, choroid, retina and retinal blood vessels). Starting on day 0, additional gross ocular examinations were performed weekly on beagle dogs in all studies, primarily to monitor signs of eye irritation (e.g., secretions and redness) and general health.

Once tear collection was complete, the test strips were placed in a microcentrifuge tube on dry ice and stored at-20 ℃. The samples were thawed, centrifuged and diluted in water prior to analysis and extracted.

The concentration of dexamethasone in the samples taken was analyzed using a validated method consisting of High Performance Liquid Chromatography (HPLC) and triple quadrupole mass spectrometer. The HPLC-MS/MS system consisted of a Shimadzu AD10vp pump, a CTC autosampler, and an ABI2000 tandem mass spectrometer controlled by Analyst 1.4.2 software. The lower limit of the amount was 1.0ng/mL. The method is linear (R = 0.998), accuracy (recovery) in the curve range is 91% to 104%, and method precision is a coefficient of variation of 5% to 7%.

The median concentration of dexamethasone in tears for each study time point for hydrogel punctal plugs loaded with 10%, 20%, and 40% dexamethasone is shown in figure 5. The median concentration of dexamethasone in 10% dexamethasone loaded hydrogel punctal plugs was 3152ng/mL after 6 hours of insertion, 1613ng/mL at day 7, and gradually decreased to about 0ng/mL at day 14. The median concentration of dexamethasone in the 20% dexamethasone-loaded hydrogel punctal plugs was 2852ng/mL on day 7, and gradually decreased to about 0ng/mL on day 28. The median concentration of dexamethasone in the hydrogel punctal plugs loaded with 40% dexamethasone was 5520ng/mL after 6 hours of insertion, gradually decreasing to 3531ng/mL on day 28 and to about 0ng/mL on day 60.

No ocular toxicity or elevated intraocular pressure was observed in all ophthalmic and ocular examinations. All hydrogel intraductal plugs were stable in the canaliculi of beagle dogs before the end of the experiment, and did not slide out or degrade.

The inventor also carried out in vitro dissolution experiments and pharmacokinetic studies in beagle dogs on hydrogel lacrimal canaliculus plugs loaded with 15% brimonidine tartrate and evaluated safety. In vitro, the hydrogel lacrimal canaliculus plug stably and slowly releases brimonidine tartrate within 14 days; in the beagle lacrimal canaliculus, the intrapunctal plug steadily and slowly released brimonidine tartrate to the tear film within 14 days, gradually decreased from 2873ng/mL to 0ng/mL, and no ocular toxicity or increase in intraocular pressure was observed.

The present invention is illustrated by the above description and examples, which are not intended to be limiting and do not limit the scope of the claims.

It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.

Claims (10)

1. An ophthalmic hydrogel composition having a controlled biodegradation time, the ophthalmic hydrogel composition characterized by: the hydrogel composition comprises a drug that will gradually dissolve in the tear fluid and be released to the eye continuously, and a polymer network comprising 2 different polyethylene glycol (PEG) units: a first PEG unit for adjusting an internal pore size and a degree of cross-linking of the polymer network, and a second PEG unit constituting a main body of the polymer network.

2. The hydrogel composition of claim 1, wherein: wherein the first PEG unit comprises a plurality of multi-arm PEG units having 2 to 10 arms; and/or, wherein the second PEG unit comprises a plurality of multi-arm PEG units having 4 to 10 arms.

3. The hydrogel composition of claim 1 or claim 2, wherein: wherein the molar ratio of the first PEG unit to the second PEG unit is between 0 and 5.

4. The hydrogel composition according to any one of claims 1 to 3, wherein: wherein the polymer network is formed by reacting a plurality of PEG units, preferably a first PEG unit selected from sazegsaz (20K), SAPPEGSAP (20K), SGPEGSG (20K) or SSPEGSS (20K), with a second PEG unit selected from 4a20KPEGSAZ, 4a20kpeg SAP, 4a20KPEGSG, 4a20KPEGSS, 8a20KPEGSAZ, 8a20KPEGSAP, 8a20KPEGSG or 8a20KPEGSS, with one or more PEG or ornithine based amine groups selected from NH2PEGNH2 (20K), 4a20KPEGNH2, 8a20KPEGNH2 or polyornithine or a salt thereof.

5. The hydrogel composition according to any one of claims 1 to 4, wherein: wherein the polymer network is amorphous under aqueous conditions, or wherein the polymer network is semi-crystalline in the absence of water.

6. The hydrogel composition according to any one of claims 1 to 5, wherein: wherein the polymer network further comprises a color developer effective to provide visibility of the hydrogel composition to the unaided human eye, preferably wherein the color developer is chemically linked to the polymer network.

7. The hydrogel composition according to any one of claims 1 to 6, wherein: wherein the drug is homogeneously dispersed within the polymer network, preferably wherein the drug is continuously delivered to the eye over a period of about 12 hours to 90 days.

8. The hydrogel composition according to any one of claims 1 to 7, wherein: wherein the drug substance is micronized, preferably the drug substance has a micronized particle size range D ₉₇ ＝2-50μm。

9. The hydrogel composition according to any one of claims 1 to 8, wherein: wherein the hydrogel composition spontaneously degrades in water by chemical hydrolysis; or, wherein the hydrogel composition does not degrade until the drug is completely released; or, wherein the hydrogel composition is naturally degraded and then expelled or manually removed; alternatively, the hydrogel is an intraluminal lacrimal plug.

10. Use of the hydrogel composition of any one of claims 1 to 9 for the preparation of an ophthalmic medicament.

Images