ES2705477T3 - Contact drug administration system - Google Patents

Abstract

A method for preparing a drug delivery system, comprising: a) synthesizing or selecting a functionalized monomer or monomers by identifying receptor sites or molecules associated with a target biological tissue to be treated with a medicament, wherein the functionalized portions of the functionalized monomer or monomers are synthesized to look chemically and / or structurally to receptor sites or molecules that are associated with the biological mechanism of action of the drug; b) forming a recognizable polymeric hydrogel, wherein the formation of the polymeric hydrogel comprises forming a solution comprising amounts of a drug, the functionalized monomer or monomers and a crosslinking monomer and initiating the copolymerization of the functionalized monomer or monomers and the monomer of crosslinking and c) forming the polymeric hydrogel in contact lenses.

Description

DESCRIPTION

Contact drug administration system

Field of the invention

The invention relates to drug delivery systems. More specifically, this invention relates to systems and an extended release ophthalmic administration method using contact lenses.

BACKGROUND OF THE INVENTION

The administration of medicaments through contact lenses has been a predominant notion since the beginning of the use of crosslinked and hydrophilic polymer gels on the surface of the eye. In fact, the first patent in the field of Otto Wichterle in 1965 states that "bacteriostatic, bactericidal or otherwise medicinal substances such as antibiotics can be dissolved in the aqueous component of hydrogels to provide drugs for a prolonged period, by diffusion" . However, there is evidence that this notion of a component dissolved in an aqueous component has existed for a much longer period of time. There is evidence that linen soaked with honey was used in ancient Rome as an ophthalmic dressing in the treatment of diseases.

The greatest obstacle to using the fluid entrained in the aqueous portion of the polymeric gel is to maintain a significant concentration of drug within the fluid to have a therapeutically relevant effect, which is ultimately limited by the solubility of the drug. This has been the main reason why the release of drugs from contact lenses has not become a clinical or commercial success. To an equivalent extent, control over the profile of drug administration and a prolonged release profile is also important for therapeutic success and has not been demonstrated with these methods. The uptake and release of the drug by means of conventional soft contact lenses (ie, currently available) can lead to a moderate intraocular concentration of the drug for a very short period of time, but does not work very well due to a lack of charge of the drug. enough drug and to control deficient release. The use of soft contact lenses and biomimetic carriers (ie, recognizable polymeric hydrogels) described herein has the potential to greatly improve ocular drug delivery by providing a significant, designed and adaptable increase in drug loading within of the carrier, as well as a prolonged and sustained release with an increase in bioavailability, less eye tissue irritation, as well as reduced ocular and systemic side effects.

The ocular bioavailability of the drugs applied to the eye is very deficient (that is, there is normally an absorption of less than 1 to 7% of the applied drug and the rest enters the systemic circulation). Factors such as ocular protection mechanisms, nasolacrimal drainage, eye effusion, lacrimation and tear renovation, metabolic degradation and non-productive adsorption / absorption, etc., result in drug malabsorption in the eye . Currently, the most efficient ocular delivery is based on improving the bioavailability of the drug by extending the supply and / or increasing the transport of the drug through the eye barriers (for example, the cornea, a transparent window with a dome shape that covers the front part of the eye, the sclera, the hard, opaque, and white part of the eye, and the conjunctiva, a mucous membrane of the eye with a highly vascularized stroma that covers the visible part of the sclera. The eye is dispersed in the tear film and can be removed by several mechanisms, such as:

(i) irritation caused by topical application, the administration vehicle or the drug that induces lacrimation that leads to drug dilution, drainage and drug loss through the nasolacrimal system in the nasopharynx and the systemic circulation ( example, the drainage rate increases with volume);

(ii) normal tearing and tear exchange (16% of the volume of tears per minute in humans under normal conditions); (iii) metabolic degradation of the drug in the tear film; (iv) corneal absorption of the drug and transport; (v) conjunctive absorption of the drug and sclerotic transport; (vi) "non-productive" conjunctive absorption through the highly vascularized stroma that gives rise to the systemic circulation; and (vii) absorption of the eyelid vessel that results in systemic circulation.

Therefore, due to these mechanisms, a relatively low proportion of the drug reaches the ocular tissue of the anterior chamber through productive routes such as mechanisms (iv) and (v).

For posterior ocular tissue and diseases of the back of the eye (eg, age-related macular degeneration, retinal degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa, etc.), the amount of drug administered may be much lower in comparison with a frontal disease of the eye. To treat the disease of the back of the eye, four methods have usually been used, topical, oral (systemic administration), intraocular and periocular administration.

Topically applied drugs diffuse through the tear film, the cornea / sclera, the iris, the ciliary body, and the vitreous before reaching the posterior tissues, but due to transport resistances Aggregates do not usually result in therapeutically relevant drug concentrations. However, researchers have shown that topical medications penetrate through the sclera by blocking the absorption and transport of the cornea. Intravitreal injections (injections into the eye) require repeated injections and have potential side effects (hemorrhage, retinal detachment, cataracts, etc.) along with low patient compliance. Long-acting devices have been used, but require intraocular surgery and often have the same incidence of side effects. The periocular administration of drugs is less invasive and also requires injections or placement of implants for a predominantly transesclerotic administration.

To overcome most of these protection mechanisms, topical formulations have been kept effective by administering very high concentrations of medication several times a day. For a large number of medications, high concentrations can cause negative effects such as burning, itching, roughness, etc., by exposing the medication to the surface of the eye, as well as increased toxicity and increased ocular side effects. systemic However, traditional ophthalmic dosage forms, such as solutions, suspensions and ointments, account for 90% of the formulations available in the market today. Solutions and suspensions (for less water-soluble drugs) are more commonly used because of ease of production and the ability to filter and sterilize easily. Ointments are used to a much lesser degree due to blurred vision, difficulty in application to the ocular surface and fat. The term "eye drops" herein is meant to refer to all topological medicaments administered to an eye surface, including, among others, solutions, suspensions, ointments and a combination thereof. In addition to the problems mentioned above, the administration of the drug by the use of eye drops does not allow the controlled release of the drug. Drugs for eye drops generally have a low residence time of the drug on the surface of the eye.

The effectiveness of topical solutions has been enhanced by viscosity enhancers that increase the residence time of drugs on the surface of the eye, which ultimately leads to greater bioavailability as well as more comfortable formulations. In addition, inclusion complexes have been used for poorly soluble drugs, which increase solubility without affecting permeation.

Other recent administration methods have included in situ gel forming systems, penetration enhancers or corneal permeation, conjunctival mucoadhesive polymers, liposomes and ocular inserts.

The ocular inserts, in some cases, achieve a relatively stable or constant release of the drug. For example, ocular inserts such as Ocusert® (Alza Corp., approved by the FDA in 1974) consist of a small drug reservoir wafer enclosed by two ethylene-vinyl acetate copolymer membranes, which are placed on the edge of the eye and provide prolonged release of a therapeutic agent for about 7 days (i.e., pilocarpine HCl, for the treatment of glaucoma which reduces intraocular pressure of the eye by increasing drainage of the fluid). Lacrisert (Merck) is a cellulose-based polymer insert used to treat dry eyes. However, inserts have not found widespread use due to the occasional warning or inadvertent expulsion of the eye, rupture of the membrane (with a peak of administration of the drug released), an increase in price with respect to conventional treatments, etc. .

Mucoadhesive systems and in situ forming polymers often have problems involving the anchoring of the carrier, as well as ocular irritation, which causes blinking and tear production. Penetration enhancers can cause transient irritation, alter normal eye protection mechanisms and some agents can cause irreversible damage to the cornea.

Lorenzo-Alvarez et al. (J Pharm. Sci., Vol. 91, no.10, October 1, 2002) refers to soft contact lenses capable of a sustained supply of timolol. Specifically, Lorenzo-Alvarez et al. teaches the influence of the composition and applications of a printing technique on the chargeability of hydroxyethyl methacrylate hydrogels weakly crosslinked with a view to their use as soft contact lenses for the administration of timolol. HIRATANI, H. ET AL. (J. CONTRL. REL., Vol. 83, July 1, 2002) describes a printing method for the preparation of contact lenses containing timolol. This method involves the formation of complexes between the assemblies of monomeric targets and timolol. The new soft biomimetic contact lens supports proposed in this work will provide a significant increase in the loading of the drug within the gel, as well as a prolonged and sustained release. This will lead to a prolonged pharmacological activity and greater bioavailability, reduced systemic absorption, reduced ocular and systemic side effects, and greater compliance on the part of the patient due to the reduction of the frequency of the medication and a lesser irregularity of the administration. (ie, the volume of eye drops depends on the angle, the compression force, etc., and it has been verified experimentally that it is highly variable). They can also be easily placed, in addition to being easily removed with or without use to correct the visual disability. Since they will be placed on the cornea, this will also result in increased permeability of the cornea.

Summary of the invention

The present invention is directed to a method for preparing a drug delivery system, the method comprising:

a) synthesizing or selecting a functionalized monomer or monomers by identifying receptor sites or molecules associated with a target biological tissue to be treated with a medicament, wherein the functionalized portions of the functionalized monomer or monomers are synthesized to look like chemical and / or structurally to receptor sites or molecules that are associated with the biological mechanism of action of the drug;

b) forming a recognizable polymeric hydrogel, wherein the formation of the polymeric hydrogel comprises forming a solution comprising amounts of a drug, the functionalized monomer or monomers and a crosslinking monomer and initiating the copolymerization of the functionalized monomer or monomers and the monomer of reticulation; Y

c) forming the polymeric hydrogel in contact lenses.

The present invention further relates to a contact lens formed from a recognizable polymeric hydrogel matrix, said polymeric hydrogel matrix which is formed of:

a) a functionalized monomer or monomers synthesized or selected by identifying receptor sites or molecules associated with a target biological tissue to be treated with a drug, wherein the functionalized portions of the functionalized monomer or monomers are synthesized to be chemically and / or structurally or mimic the receptor sites or molecules that are associated with the biological mechanism of action of the drug;

b) a drug; Y

c) a crosslinking monomer;

for use in dispensing the medication to a biological tissue.

The drug delivery system includes a recognizable polymeric hydrogel through which a drug is administered by contact with biological tissue. The recognizable polymeric hydrogel is formed using a drug, functionalized monomers, preferably having complexing sites, and crosslinking monomers, which are copolymerized using a suitable initiator, as described in detail below. The complexing sites of the recognizable polymeric hydrogel that is formed preferably mimic the target biological tissue receptor sites, the biological recognition or the biological mechanism of action. The system unifies what in the present document is called a recognizable biomimetic polymeric hydrogel.

The system according to one embodiment is a contact lens ophthalmic drug system. The ophthalmic drug system includes soft contact lenses formed from the recognizable biomimetic polymer hydrogel and which are impregnated with a drug that can be released for a period of time while in contact with the eyes. The invention is directed to both corrective or refractive contact lenses and non-corrective or non-refractive contact lenses. According to the embodiments of the invention, a hydrogel matrix is formed from silicon-based crosslinking monomers, carbon or organic-based monomers, macromers or a combination thereof. Suitable crosslinking monomers include, but are not limited to, polyethylene glycol (200) dimethacrylate (PEG200DMA), ethylene glycol dimethacrylate (EGDMA), tetraethylene glycol dimethacrylate (TEGDMA), N, N'-methylene-bis-acrylamide and polyethylene glycol dimethacrylate (600) (PEG600DMA). Suitable silicon-based crosslinking monomers may include tris (trimethylsiloxy) silylpropyl methacrylate (TRIS) and hydrophilic derivatives of TRIS such as tris (trimethylsiloxy) silyl propylvinyl carbamate (TPVC), tris (trimethylsiloxy) silyl propyl glycerol methacrylate (SIGMA), tris (trimethylsiloxy) silyl propyl methacryloxyethyl carbamate (TSMC); polydimethylsiloxane (PDMS) and PDMS derivatives, such as the methacrylate-end fluorinated PDMS crosslinker, a urethane-siloxane copolymer crosslinker with methacrylate end, a styrene-end capped siloxane polymer containing polyethylene and polypropylene oxide; and siloxanes containing hydrophilic grafts or grafts of amino acid residues, and siloxanes containing hydrophilic blocks or containing grafts of amino acid residues. The molecular structure of these monomers can be altered chemically to contain residues that match amino acid residues or other biological molecules. In cases where the above monomers, when polymerized with hydrophilic monomers, a solubilizing cosolvent, such as dimethyl sulfoxide (DMSO), isopropanol, etc. can be used. or a protective / unprotective group strategy.

The amounts of crosslinking monomer may be (from 0.1 to 40%, moles of crosslinking monomer / moles of all monomers); functional monomers, from 99.9% to 60% (moles of functional monomers / moles of all monomers) with varying relative portions of multiple functional monomers; initiator concentration ranging from 0.1 to 30% by weight; solvent concentration ranging from 0% to 50% by weight (but is preferred without solvent); ratio of monomer to biological template (M / T) ranging from 0.1 to 1000, reference reference 950 for the ketotifen polymers presented herein, in a nitrogen or air environment (in air,% by weight of initiator must be increased above 10% by weight)

The ophthalmic drug delivery system also includes a drug, ie, drug molecules, prodrugs, proteins, amino acids, protein drugs, oligopeptides, polypeptides, oligonucleotides, ribonucleic acid, deoxyribonucleic acid, antibody or other biologically active compound. This also includes a medicine with an attached biological template. The drug is preferably linked to the hydrogel matrix through one or more of the electrostatic interactions, hydrogen bonds, hydrophobic interactions, coordination complexation and Van der Waals forces.

The medicaments are preferably weakly bound to a hydrogel matrix through functionalized monomer units, macromer units or oligomer units that are copolymerized in the hydrogel matrix to form receptor locations within the hydrogel matrix that resemble or mimic the receptor sites or molecules associated with the target biological tissue to be treated with the drug or the biological mechanism of action.

In accordance with embodiments of the invention, a portion of the drug can be washed from the recognizable hydrogel polymer, loaded with a drug. The polymerization reaction forms a contact lens. For example, the gel is polymerized in a mold or compression molded. Once the contact lenses are formed, they can be used to administer the medication through contact with the eyes. Alternatively, the recognizable hydrogel polymer can be formed into contact lenses, washed to remove a portion of the medicament and then loaded with the medicament. When the biological template is the medicine, the washing step can be lighted or truncated. The free base form of the drug or the hydrochloride salt of the drug can be used.

According to the method of the present invention, a recognizable biomimetic polymer hydrogel is formed by making a mixture or solution including amounts of a drug, monomer or functionalized monomers, crosslinking monomer or monomers and polymerization initiator in a suitable solvent or without solvent . Suitable initiators include water-soluble initiators and are not soluble in water, but are not limited to azobisisobutyronitrile (AIBN), 2,2-dimethoxy-2-phenyl acetophenone (DMPA), 1-hydroxycyclohexylphenyl ketone (Irgacure® 184), 2.2 -dimethoxy-1,2-diphenyletan-1-one (Irgacure 651), ammonium persulfate, iniferter such as tetraethylthiuram disulfide, or combinations thereof. The polymerization can be initiated photonically, it can be thermally initiated, it can be initiated by redox or a combination of its combinations.

The functionalized monomer or monomers are complexed with the drug and copolymerized with crosslinking monomer or monomers to form a recognizable biomimetic polymer hydrogel, as described above. The functional monomers or reagents useful herein are those that possess chemical or thermodynamic compatibility with a desired drug. As used herein, the term "functional monomer" includes moieties or chemical compounds in which there is at least one double bond group that can be incorporated into a growing polymer chain by chemical reaction and one terminus having a functionality that will interact with the drug through one or more of electrostatic interactions, hydrogen bonds, hydrophobic interactions, coordination complexion and Van der Waals forces. Functional monomers include macromers, oligomers, and polymer chains with pendant functionality and which have the ability to crosslink to create the recognizable hydrogel. The crosslinking monomer includes chemicals with multiple double bond functionality that can be polymerized in a polymer network. Examples of functionalized monomers include, but are not limited to, 2-hydroxyethyl methacrylate (HEMA), acrylic acid (AA), acrylamide (AM), N-vinyl 2-pyrrolidone (NVP), 1-vinyl-2-pyrrolidone (VP) ), methyl methacrylate (MMA), methacrylic acid (MAA), acetone acrylamide, 2-ethyl-2- (hydroxymethyl) -1,3-propanediol trimetacrylate, N- (1,1-dimethyl-3-oxobutyl) acrylamide, -ethyl-2- (hydroxymethyl) -1,3-propanediol trimetacrylate, 2,3-dihydroxypropyl methacrylate, allyl methacrylate, 3- [3,3,5,5,5-pentamethyl-1,1-bis [pentamethyldisiloxanyl] oxis ] trisyloxanyl] propyl methacrylate, 3- [3,3,3-trimethyl-1,1-bis (trimethylsiloxy) disiloxanyl] propyl methacrylate (TRIS), N- (1,1-dimethyl-3-oxybutyl) acrylamide, itaconate dimethyl, 2,2,2-trifluoro-1- (trifluoromethyl) ethyl methacrylate, 2,2,2-trifluoroethyl methacrylate, methacryloxypropylbis (trimethylsiloxy) methylsilane, methacryloxypropylpentamethyldisiloxane, (3-methacryloxy-2-hydroxypropyloxy) propylbis (trimethylsiloxy) methylsilane, 4-t-butyl-2-hydroxycyclohexy methacrylate, dimethylacrylamide and glycerol methacrylate. Once formed, the recognizable biomimetic polymer hydrogel can be formed in contact lenses or, as described above, the polymerization reaction forms contact lenses.

According to further embodiments of the invention, the functionalized monomers are synthesized or selected by identifying receptor sites or molecules associated with the target biological tissue to be treated by the drug or that are associated with the metabolization of the drug. Then, the functionalized portions of the functionalized monomers are synthesized to resemble or mimic chemically and / or structurally the receptor sites or molecules that are associated with the biological mechanism of action of the drug. These functionalized monomers are then copolymerized with the crosslinking monomer or monomers used to form the hydrogel matrix, as described above.

After the medication has been exhausted from the contact lenses through the eyes, the contact lenses can be reloaded with the drug by soaking the contact lenses in the reconstituting medication solution. Although contact lenses have been described in detail as those used to administer antihistamines and other allergy medications, the ophthalmic systems and methods of Administration of drugs of the present invention can be used to administer any number of drugs through contact with the eye.

Medicaments that can be administered by the system of the present invention include, among others, antibacterial, anti-infective and antimicrobial agents (referred to as antibiotics) such as penicillins (including aminopenicillins and / or penicillins with inhibitor of the penicillinase), cephalosporins (and the closely related cepamycins and carbapenems), fluoroquinolones, tetracyclines, macrolides, aminoglycosides. Specific examples include, but are not limited to, erythromycin, zinc bacitracin, polymyxorazonine, polymyxin B sulfate, neomycin, gentamicin, tobramycin, gramicidin, ciprofloxacin, trimethoprim, ofloxacin, levofloxacin, gatifloxacin, moxifloxacin, norfloxacin, sodium sulfacetamide, chloramphenicol. , tetracycline, azithromycin, clarithromycin, trimethoprim sulfate and bacitracin.

The ophthalmic drug delivery system and the method of the present invention can also be used to administer non-steroidal anti-inflammatory agents (NSAIDs) and steroids (so-called anti-inflammatory agents) which include inhibitors of both COX-1 and COX-2. Examples include, but are not limited to, corticosteroids, medrysone, prednisolone, prednisolone acetate, prednisolone sodium phosphate, fluorametolone, dexamethasone, betamethasone sodium phosphate, fluoromethasone, antazoline, fluorometholone acetate, rimexolone, loteprednol etabonate, diclofenac ( diclofenac sodium), ketorolac, ketorolac tromethamine, hydrocortisone, bromfenac, flurbiprofen, antazoline and xylometazoline.

The ophthalmic drug delivery system of the present invention can also be used to administer antihistamines, mast cell stabilizers and anti-allergic agents (generally referred to as antihistamines). Examples include, but are not limited to, cromolyn sodium, iodoxamide tromethamine, holopatadine HCl, nedocromil sodium, ketotifen fumarate, levocabastine HCl, azelastine HCl, pemirolast (pemirolast potassium), epinastine HCl, naphazoline HCl, emedastine, antazoline, pheniramine, sodium cromoglycate, N-acetyl-aspartyl glutamic acid and amlexanox.

In still other embodiments of the invention, the ophthalmic drug delivery system is used to administer antiviral agents including, but not limited to, trifluridine and vidarabine; anti-cancer therapeutic products including, but not limited to, dexamethasone and 5-fluorouracil (5FU); local anesthetics including, inter alia, tetracaine, proparacaine HCl, and benoxinate HCl; cycloplegic and mydriatic including, among others, atropine sulfate, phenylephrine HCl, cyclopentolate HCl, scopolamine HBr, homatropine HBr, tropicamide and hydroxamfetamine HBr; comfort molecules or molecules (generally referred to as lubricating agents) to treat Keratoconjunctivitis sicca (dry eye), which include, among others, hyaluronic acid or hyaluronan (of variable molecular weight, MW), hydroxypropylcellulose (of variable MW), gefarnate, hydroxycosatetranenoic acid (15- (S) -HETE), derivatives of phospholipids-HETE, phosphoylkylcholine or other polar lipids, carboxymethylcellulose (of variable MW), polyethylene glycol (of variable MW), polyvinyl alcohol (of variable MW), rebamipide, pimecrolimus , hydrophilic and sodium unsolbed polymers; immunosuppressive and immunomodulatory agents including, but not limited to, cyclosporin, tacrolimus, anti-IgE and cytokine antagonists; and anti-glaucoma agents including beta-blockers, pilocarpine, direct-acting miotics, prostagladins, alpha-adrenergic agonists, carbonic anhydrase inhibitors, including but not limited to betaxolol HCl, levobunolol HCl, metipranolol HCl, maleate or timolol hemihydrate. , Carteolol HCl, carbachol, pilocarpine HCl, latanoprost, bimatoprost, travoprost, brimonidine tartrate, apraclonidine HCl, brinzolamide and dorzolamide HCl; decongestants and vasoconstrictors that include, among others, epinephrine and pseudoephedrine. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a block diagram showing the steps for preparing contact lenses, according to the embodiments of the invention.

Figure 2 illustrates the formation of a recognizable polymeric hydrogel, according to embodiments of the invention.

Figure 3 illustrates a block diagram describing the steps for preparing a functionalized monomer used in the synthesis of recognizable polymeric hydrogels, in accordance with embodiments of the invention. Figures 4A-C illustrate examples of groups of molecules that coincide, resemble or mimic each other.

Figures 5A-B are graphs comparing the equilibrium isotherms of ketotifen in water for a recognizable polymer hydrogel and a control hydrogel.

Figures 5C are drug loading graphs for recognizable polymeric hydrogels of the present invention against control hydrogels to show improved drug loading for recognizable polymeric hydrogels of the present invention.

Figure 6 shows a graph of the drug release profiles for therapeutic contact lenses, according to the embodiments of the invention.

Figures 7A-B show charts of entrainment release profiles for recognizable polymeric hydrogels, in accordance with embodiments of the invention.

Detailed description of a preferred embodiment

Hydrogels are network structures of crosslinked, insoluble polymers, homo-co-polymer compounds or hydrophilic hetero-co-polymers, which have the capacity to absorb significant amounts of water. Consequently, this is an essential property to achieve an immunotolerant surface and matrix (i.e., with respect to protein adsorption or cell adhesion). Due to their important water content, hydrogels also have a degree of flexibility very similar to natural tissue, which minimizes the potential irritation of the surrounding membranes and tissues.

The hydrophilic and hydrophobic balance of a gel carrier can be altered to provide adjustable contributions that exhibit different solvent diffusion characteristics, which in turn influence the diffusive release of a drug contained within the gel matrix. In general, a hydrophilic monomer can be polymerized with other less hydrophilic or more hydrophobic monomers to achieve the desired swelling properties.

These techniques have resulted in a wide range of inflatable hydrogels. The knowledge of the swelling characteristics is of great importance in biomedical and pharmaceutical applications, since the degree of swelling equilibrium influences the diffusion coefficient through the hydrogel, the surface properties and the mobility of the surface, the mechanical and optical properties. The release of the drug depends on two processes of simultaneous velocity: the migration of the water to the network and the diffusion of the drug outwards through the swollen gel.

Soft contact lenses are made of hydrogels. The typical properties of contact lens materials involve a series of considerations such as optical quality (good transmission of visible light), high chemical and mechanical stability, manufacturing capacity at a reasonable cost, high oxygen transmissibility, wettability of the tear film for comfort and resistance to the accumulation of protein and lipid deposits, as well as an adequate cleaning and disinfection scheme.

Soft contact lenses usually consist of poly (2-hydroxyethyl methacrylate) (PHEMA). Other lens materials include HEMA copolymerized with other monomers such as methacrylic acid, acetone acrylamide and vinylpyrrolidone. In addition, copolymers of vinyl pyrrolidone and methyl methacrylate are commonly used, as well as copolymers of glycerol methacrylate and methyl methacrylate. Secondary ingredients have included a variety of other monomers, as well as crosslinking agents.

The soaking and soaking of soft contact lenses in drug solutions has shown promise in increasing the bioavailability of the drug with a minimization of side effects. However, the materials and the constitutive chemistry of the macromolecular chains and the subsequent interaction with the drugs are random and, in general, result in a deficient drug load.

In order to address the aforementioned drawbacks, the present invention is directed to the use of biomimetic printing of hydrogels to prepare arrays of hydrogels that can selectively bind a drug through complex sites that result in improved loading of a drug and a controlled release over time of the drug. These hydrogels are called recognizable polymeric hydrogels. The polymerization reaction forms contact lenses, which can be used to administer medications through contact with the eyes, thus replacing traditional eye drops therapies. Alternatively, recognizable polymeric hydrogels can be formed or transformed into contact lenses that can be used to deliver drugs through eye contact, thus replacing traditional eye drop therapies or other delivery mechanisms.

For example, ketotifen fumurate is a potent, highly selective, fast-acting histamine H1 antagonist with sustained duration of action. Levocabastine and ketotifen fumurate inhibit itching, redness, swelling of the eyelids, lacrimation and chemosis induced by the provocation of the conjunctiva with allergens and histamine. With topical application in the form of eye drops, absorption is incomplete and bioavailability is low. Thus, the dose is usually administered several times a day. In addition, due to a high concentration of drug and other constituents of the ophthalmic suspension preparation, patients are advised not to wear soft contact lenses. Therefore, a soft contact lens that could be used to administer ketotifen fumurate would not only increase the effectiveness of the treatment, but would also allow allergic people to wear contact lenses.

Referring to Figure 1, which is a block diagram 100 describing the steps for preparing contact lenses, in accordance with the embodiments of the invention and Figure 2, which is a graphic representation of the formation of a recognizable polymeric hydrogel 221. In step 101, the recognizable hydrogel matrix 221 is formed. The recognizable hydrogel 221 is formed by generating a solution 200 comprising one or more drugs 201, one or more functionalized monomers 203 and 203 ', one or more crosslinking monomers 205 with or without a solvent. In the 200 'solution, the functionalized monomers 203 and 203' form complexes with the drugs 201. A suitable initiator or mixing initiators 207 are used to copolymerize the functionalized monomers 203 and 203 'with a crosslinking monomer 205 to form the charged hydrogel 220 comprising a hydrogel matrix 221 with drugs 201 that complex at site 209 through the hydrogel matrix 221.

Preferably, the drugs are complexed with the hydrogel matrix 221 through weak or non-covalent interactions, as explained above, whereby the biological templates can be washed or rinsed from the complexed hydrogel 220 to form a recognizable, non-complexed polymeric hydrogel 221, which has empty complexation sites 209 that can be used to complex drug molecules that are structurally and / or chemically similar to drugs 201. It will be clear from the discussions before and after that it may not be necessary to wash the Hydrogel matrix 221 drugs for all drug delivery systems that are synthesized.

Still referring to both of Figure 1 and Figure 2, after the recognizable hydrogel 221 is formed, in step 101, in step 103 the recognizable hydrogel 221 can be formed in contact lenses using any technique known in the art. It is understood that step 103 is not necessary, when the polymerization reaction forms contact lenses, as described above. The contact lenses can be placed in contact with the eyes in step 107 to administer or deliver the medicament through the eyes. When medicament 201 has been washed from the recognizable hydrogel matrix before or after step 103 of forming the contact lenses of the recognizable hydrogel matrix, then in step 109 or step 105, respectively, the hydrogel matrix recognizable or contact lenses will be loaded with a medication. The recognizable hydrogel matrix or contact lenses can be loaded with the drug by soaking the recognizable hydrogel matrix or contact lenses in an aqueous solution of drug.

Now referring to Figure 2 and Figure 3. In accordance with further embodiments of the invention prior to the step of preparing an ophthalmic drug delivery system, such as described with reference to Figure 1, in step 301, the target tissue to be treated with the drug or the biological mechanism of action is studied to determine the types of molecules or functional groups that are associated with the action of the drug in the target tissue to affect the target tissue. Based on this information, in step 303, the functionalized monomers are synthesized with functional groups that mimic or resemble molecules or functional groups that are associated with the action of the drug on the target tissue. Monomers functionalized with the functional groups that mimic or resemble the molecules or functional groups that are associated with the metabolization of the drug in the target tissue are used to synthesize a drug delivery system, as described above with reference to FIG. 1. The biomimetic approach is the process of mimicking biological recognition or exploiting biological mechanisms. Specifically, it is the process of coordinating molecular biological recognition, interactions or actions to design materials that can be structurally similar and / or function similar to biological structures.

Figures 4A-C illustrate examples of groups of molecules that coincide, resemble or mimic each other. With reference to the biomimetic approach to synthesize recognizable hydrogel polymers described above, acrylic acid can be used to mimic aspartic acid (Fig. 4A), acrylamide can be used to mimic asparagine (Fig. 4B) and N-vinylpyrrolidinone can be used to mimic tyrosine (Fig. 4C). It is known that aspartic acid, asparagine and tyrosine belong to the group of amino acids that provide the non-covalent interactions in the binding bag of the ligand for histamine. For example, the structural analysis of the ligand binding bags and the amino acids involved in multiple non-covalent binding sites provide one of the many rational frameworks for synthesizing recognizable networks from functional monomers. It has been shown that the antihistamine binds more closely and has a higher affinity than histamine for the histamine binding pocket.

Example

Materials and methods: Acrylic acid (AA), acrylamide (AM), N-vinyl-2-pyrrolidone (NVP) and 2-hydroxyethyl methacrylate (HEMA), azobisisobutyronitrile (AIBN) and ketotifen fumarate were purchased to Sigma-Aldrich. Polyethylene glycol (200) dimethacrylate (PEG200DMA) was purchased from Polysciences, Inc. All chemicals were used as received. Polymer and copolymer networks were prepared using various mixtures of the above monomers (e.g., poly (A ^a - ^co- AM-HEMA-PEG200 ^d M ^a ), poly (AA-co-HEMA-co-PEG200 DMA), poly (AM-co-HEMA-co-PEG200DMA), poly (AA-co-AM-co-NVP-co-HEMA-PEG200DMA)). The current work is aimed at the production of nets that can also be used in the formation of contact lenses for antihistamines with monomers and copolymers of molecules such as N-vinyl-2-pyrrolidone (NVP), 1-vinyl-2-pyrrolidone (VP), methyl methacrylate (MMA), methacrylic acid (MAA), acetone acrylamide, ethylene glycol dimethacrylate (EGDMA), 2-ethyl-2- (hydroxymethyl) -1,3-propanediol trimetacrylate, N- (1,1-dimethyl) -3-oxobutyl) acrylamide, 2-ethyl-2- (hydroxymethyl) -1,3-propanediol trimetacrylate, 2,3-dihydroxypropyl methacrylate, allyl methacrylate, and other suitable monomers, such as those mentioned above.

Precise amounts of monomers, template molecules and crosslinkers were added in that order, and the mixture was sonicated to obtain a homogeneous solution. In particular, a typical formulation consisted of 5 mol% crosslinking monomer (PEG200DMA) in a solution of acrylamide (M), HEMA (M), ketotifen (T), with an M / T ratio of about 950 ( 92% HEMA, 1% of the remaining monomers, and approximately 1% by mole of medicine depending on the M / T ratio). The controls were also prepared without the template. Next, the AIBN initiator was added under low light conditions, and the solutions were allowed to equilibrate for 12 hours in the dark. This step allowed the monomers and the template to orientate and reach their minimum of free energy, thus beginning the printing of configuration at the molecular level. However, this stage occurs very quickly, on the order of minutes.

The solutions were then transferred to a MBRAUN Labmaster 1301500/1000 hood, which provides a nitrogen-free, temperature-controlled inert atmosphere for free-radical photopolymerization. With an increase in% by weight of photoinitiator, this step can be carried out in the air. The solutions were uncovered and left open to nitrogen until the oxygen levels reached negligible levels (<0.1 ppm). The solutions were inserted into glass molds (6 in. X 6 in. (15 cm x 15 cm)) separated by a Teflon frame 0.8 mm wide, as measured by a Vernier calibrator. The glass plates were coated with chlorotrimethylsilane to prevent the polymer matrix from sticking to the glass, since it shows a strong adherent tendency due to hydrogen bonding. The polymerization was carried out for ten minutes at 325 V using a Dymax UV light source. The radiation intensity was 40 mW / cm2, measured with a radiometer, and the temperature was 36 ° C, measured by a thermocouple.

The polymer was detached from the glass plates with deionized water (Millipore, 18.2 mOcm, pH 6) and then allowed to soften for about 10 minutes. The circular discs were cut using a cork perforator of size 10 (13.5 mm), and were usually washed for 5 days in a continuous flow system using deionized water. All the washings proceeded until the absence of detectable drug was verified by spectroscopic monitoring. To obtain dry weights, some discs were allowed to dry under laboratory conditions (20 ° C) for 36 hours. The discs were then transferred to a vacuum oven (27 in. (686 mm) of Hg, 33-34 ° C) for 48 hours until they were dry (less than 0.1% by weight difference).

Penetration polymer uptake and swelling data were obtained in deionized water with samples taken every 5 minutes during the first hour, and then every hour for 10 hours until reaching equilibrium. When the gel was removed from the water, excess water from the surface was rubbed with a dry Kim towel. The equilibrium weight swelling ratio at time t, q, for a given gel was calculated using the weights of gels at time a and dry polymer weights, respectively, using equations based on the Archimedes buoyancy principle. Dynamic union and equilibrium template: The dynamic union of the drug molecule and the template was made until equilibrium was established for each system. Stock solutions of drug with a concentration of 2 mg / ml were prepared and diluted with deionized water to produce solutions of 0.1, 0.2, 0.3, 0.4 and 0.5 mg / ml. Each solution was vortexed for 30 seconds to provide homogeneity, and the initial UV absorbances were noted. Then gels were inserted into the vials and placed in a Stovall Belly Button orbital shaker for the entire duration of the binding cycle to provide an adequate mixture. A 200 pl aliquot of each sample was placed in a Corning Costar UV-transparent microplate, and the absorbance readings were taken using a Biotek spectrophotometer at 268 nm. After the measurement, the reading sample was returned to the original samples, to avoid fluctuations in the concentrations due to the sampling methods.

Dynamic release studies: To obtain the preliminary results, dynamic release studies were carried out in DI water, artificial lacrimal fluid (6.78 g / l NaCl, 2.18 g / l NaHCO3, 1.38 g / l KCl, 0.084 g / l of CaChH2O, pH 8) and lysozyme (1 mg / ml) in artificial tear fluid. The gels that had been loaded with drug were placed in 30 ml of DI water, and the solutions were continuously stirred with a Servodyne mixer (Cole Palmer Instrument Co.) at 120 rpm. Drug release was monitored at 268 nm by extracting 200 μl of solution in a 96 well Corning Costar UV transparent microplate, and measurements were made on a Synergy UV-Vis spectrophotometer (Biotek). Absorbances were recorded for three samples, averaged and corrected by subtracting the relevant controls. The solutions were replaced after each reading. Separate studies were conducted to determine if there were indefinite immersion conditions and those conditions were combined in all the experiments.

Kinetics of polymerization and network formation: Solutions were prepared with 0, 0.1, 0.5 and 1 mole percent ketotifen in the initial monomer solutions. Kinetic studies were performed with a differential scanning photocalorimeter (DPC, Model No. DSC Q100, TA Instruments with mercury light source). Samples of 10 pl were placed in a sealed aluminum tray and purged with nitrogen (flow rate 40 ml / min) to prevent oxidative inhibition. They were left to equilibrate at 35 ° C for 15 minutes, before making the UV light shine at 40 mW / cm2 for 12 minutes.

The heat released was measured as a function of time and the theoretical enthalpy of the monomer solution was used to calculate the polymerization rate, Rp, in fractional conversion units of double bonds per second. The Integration of the speed of the polymerization curve as a function of time produced the conversion as a function of time or reaction rate. The presence of template and a solvent, if used, was taken into account in the calculations, since it did not participate in the polymerization reaction. The experimental results were reproducible and the main source of the error involved the theoretical enthalpies assumed in the calculations of the polymerization and conversion rate. For all studies, it was assumed that the enthalpies had errors of 5%. Assumptions in the copolymerization of two monomers (ie, functional and crosslinking monomers) were that each monomer had equal reactivity and the theoretical enthalpy derived from a co-monomer mixture was an average of the enthalpies of individual monomers. The theoretical enthalpy of the methacrylate double bonds was equal to 13.1 kcal / mol and the theoretical enthalpy of the acrylate double bonds was equal to 20.6 kcal / mol.

RESULTS

FIG. 5A shows a graph 500 of the equilibrium binding isotherm for ketotifen in water for hydrogel networks of poly (acrylamide-co-HEMA-co-poly (ethylene glycol 200) dimethacrylate with a percent crosslinking of 5%. N = 3 and T = 25 ° C. The recognizable hydrogel network is represented by line 501 and the control hydrogel network is represented by line 503. The percentage represents the percentage of crosslinker in moles per mole of total monomers in feeding.

Fig. 5B shows a graph 510 of the equilibrium binding isotherm for ketotifen in water for hydrogel networks of poly (acrylic acid-co-HEMA-co-poly (ethylene glycol) 200 dimethacrylate) with a crosslinking percentage of 5% . N = 3 and T = 25 ° C. The recognizable hydrogel networks are represented by line 511 and the control hydrogel network is represented by line 513. The percentage represents the percentage of crosslinker in moles per mole of total monomers in the feed.

FIG. 5C shows an improved loading graph of ketotifen 540 for multiple monomer gels for poly (n-co-HEMA-co-poly (ethylene glycol) 200 dimethacrylate) networks. The uses of the functional monomers are acrylic acid, acrylamide, NVP or an equal mixture of moles of both. Recognizable networks are shown as striped bars 543 and control networks are shown as light bars 541.

Fig. 6 shows a graph 600 of adaptive release profiles of therapeutic contact lenses for poly (n-co-HEMA-co-poly (ethylene glycol) 200 dimethacrylate) networks in artificial tear fluid, where n is recognizable AM networks (represented by circles), AA (represented by squares), AA-AM (represented by triangles) and NVP-AA-AM (represented by diamonds), respectively. The results demonstrate an approximately constant release rate of ketotifen fumurate for 1 to 5 days.

Fig. 7A shows a plot 700 of release data for recognizable networks of poly (AM-co-HEMA-co-poly (ethylene glycol) 200 dimethacrylate). The fraction of the mass released in artificial tear solution with / without lysozyme.

Fig. 7B shows a graph 725 of release data of poly (AM-co-AA-co-HEMA-co-poly (ethylene glycol) 200 dimethacrylate). Networks of drug mass released in artificial tear solution

I. Improved loading and performance of multiple monomer mixtures

In the preliminary work, hydrogels with improved loading for ketotifen fumarate were produced. The polymers were made with the following monomers: acrylic acid (AA), N-vinyl 2-pyrrolidone (NVP), acrylamide (AM), 2-hydroxyethyl methacrylate (HEMA) and polyethylene glycol (200) dimethacrylate (PEG200DMA).

Our hypothesis is that gels composed of multiple functional monomers will outperform simple functional monomer compounds. For recognizable antihistamine polymers, this would better mimic the histamine coupling site at the molecular level, providing all the relevant functionality necessary for non-covalent interactions. We have shown that the loading properties of the gels are improved with multiple monomer mixtures.

Gels of multiple complexing points with variable functionality exceeded gels formed with less diverse functional monomers and showed the highest maximum limit of ketotifen and the greatest difference with respect to control gels. The equilibrium binding isotherms for the poly (AM-co-AA-co-HEMA-co-PEG200DMA) networks demonstrate an improved load with a factor of 2 times greater in drug loading compared to conventional networks (ie say, gels prepared without template and comparable to existing contact lenses) depending on the polymer formulation and the polymerization conditions. The poly (AM-co-HEMA-co-PEG200DMA) networks demonstrated a 2 or 100% increase factor in drug loading compared to control networks with lower limit amounts. The poly (AA-co-HEMA-co-PEG200DMA) networks show a 6-fold increase in the ketotifen loading control, with the total bound drug being the lowest of the polymer formations studies ( approximately 33% less loading of ketotifen than the network functionalized with AM).

For all systems, an increase in the amount of drug loaded has been confirmed, but with most of the biomimetic formulation (poly (AA-co-AM-co-NVP-co-HEMA-PEG200DMA)) an increase is demonstrated significant in the load producing the highest load potential (the highest load achieved to date and 6x over control networks due to multiple link points with variable functionalities) (Fig. 5C).

II. Dynamic drug release profiles

The dynamic release profiles in artificial tear solution and an artificial lacrimal solution with protein demonstrated the prolonged release of a viable therapeutic concentration of ketotifen. The release studies confirmed that the release rates can be adapted through the type and amount of functionality and can range from one to five days. Figure 6 highlights the normalized data of the fraction of drug released as a function of time (mass administered at time t divided by the mass administered at infinity time). For poly (n-co-HEMA-co-PEG200DMA) networks (where n was AA-co-AM, AM or AA), the drug release showed a relatively constant rate of release for approximately 1 day, with little difference in the release profile. However, the most structurally biomimetic network, poly (AA-co-AM-co-NVP-co-HEMA-PEG200DMA), showed a five-fold increase in the prolonged release profile (ie, approximately 5 days).

It was hypothesised that providing all relevant functionality to the coupling site mimicked with the proposed polymer synthesis technique provides a greater affinity of the drug for the network and, therefore, an even slower release of the drug compared to the control networks. In addition, a release profile of five to seven days adapts quite well to the time of use of soft contact lenses for extended use for a week.

It has been shown that the drug load can be controlled by the type, number and diversity of functionalities within the network. The charge (and, therefore, the mass delivered) can also be controlled by the initial loading concentration of the drug. We have shown control over the accumulated mass of drug released by changing the load concentration. When considering the relative size of our gels (ie, the gels were slightly larger than normal lenses) and the drug mass released compared to the typical doses of eye eye drops (ketotifen, 0.25 mg / ml of solution with one drop every 8 hours), the results revealed that a therapeutically relevant dose could be administered for long periods of time.

To investigate the effect of the protein on the dynamic release, we chose lysozyme as a model protein, since it is the largest protein component in the tear fluid. Figures 8 A-B highlight the release profile of the poly (AM-co-HEMA-co-PEG200DMA) network in artificial tear solution with lysozyme, which results in an increase of the factor 5 in the duration of the release. For the most structurally biomimetic network, poly (AA-co-AM-co-NVP-co-HEMA-PEG200DMA), this could lead to a sustained release of approximately 25 days. These studies demonstrate that the release time may be further delayed in an in vivo environment, leading to a substantial increase in the applicability of the contact lens ocular supply.

III. Analysis of the polymerization reaction

The polymerization rate for a given conversion decreased as the mole percentage of the template molecule increased in a prepolymerization monomer solution. Therefore, the formation of polymer chains and the improved charge due to the configurational biomimetic effect may be related to the propagation of polymer chains. The template molecule imposes physical restrictions on free radicals and the movement of the propagation chain and, therefore, effectively reduces the rate of polymerization in the creation of ligand binding bags. These results show that the CBIP is reflected at the molecular level. For a given conversion, the polymerization rate was lower for the multiple polymerization mixtures of functional monomers than the individual monomer mixtures.

IV Swelling profiles in equilibrium and analysis of mechanical properties:

The equilibrium swelling studies in DI water and 0.5 mg / ml of ketotifen concentrated solution indicated that the recognizable nets and control were statistically equal and that 40% of the swollen gels is water, indicating that comfort of use and the oxygen permeability of these gels is in line with conventional contact lenses. These studies indicated that the CBIP, and not a greater porosity or gel surface area, is responsible for the improved load properties. He also showed that the charging process does not affect the swelling speed of the polymer matrix.

Other studies on the mechanical properties of the gels have shown storage and loss modules, glass transition temperatures and damping factors comparable to those of conventional contact lenses (data not shown). Each gel produced was optically clear and had sufficient viscoelasticity to be molded into thin films (for refractive differences)

CONCLUSION:

The kinetics of the polymerization in the presence of the template reveals interaction mechanisms and provides criteria with which other monomer systems can be chosen experimentally. The use of a biomimetic approach to synthesize recognizable hydrogel polymers has led to the development of an ophthalmic drug delivery system using contact lenses formed from the recognizable hydrogel polymer. The ophthalmic drug delivery system of the present invention can provide improved bioavailability and efficacy of drug administration and exhibit a controlled release over time of the drug. The ophthalmic drug delivery system can be adapted to exhibit the properties suitable for the intended pharmacological therapy and has the potential to replace traditional eye drops therapies and other methods.

The present invention has been described in terms of specific embodiments that incorporate details to facilitate the understanding of the principles of construction and operation of the invention.

Claims (11)

A method for preparing a drug delivery system, comprising: a) synthesizing or selecting a functionalized monomer or monomers by identifying receptor sites or molecules associated with a target biological tissue to be treated with a medicament, wherein the functionalized portions of the functionalized monomer or monomers are synthesized to look like chemical and / or structurally to receptor sites or molecules that are associated with the biological mechanism of action of the drug; b) forming a recognizable polymeric hydrogel, wherein the formation of the polymeric hydrogel comprises forming a solution comprising amounts of a drug, the functionalized monomer or monomers and a crosslinking monomer and initiating the copolymerization of the functionalized monomer or monomers and the monomer of crosslinking and c) forming the polymeric hydrogel in contact lenses. 2. The method of claim 1, wherein the drug is selected from the group consisting of an antibiotic, an antiinflammatory, an antihistamine, an antiviral agent, a cancer drug, an anesthetic, a cycloplegic, a mydriatic, a lubricating agent, a decongestant, a vasoconstrictor, an immunosuppressant, an immunomodulatory agent, an anti-glaucoma agent and an anti-infective agent. The method of claim 1, further comprising washing a portion of the drug from the contact lenses and charging the contact lenses with a drug by soaking the contact lenses in an aqueous solution of drug. 4. The method of claim 3, wherein the drug is selected from the group consisting of an antibiotic, an antiinflammatory, an antihistamine, an antiviral agent, a cancer drug, an anesthetic, a cycloplegic, a mydriatic, a lubricating agent, a decongestant, a vasoconstrictor, an immunosuppressant, an immunomodulatory agent, an anti-glaucoma agent, an anti-infective agent and an alpha-adrenergic agonist. The method of claim 4, wherein the drug is an antihistamine and the functionalized monomers are selected to mimic aspartic acid, asparagine and tyrosine, wherein the functionalized monomers comprise acrylic acid, acrylamide and N-vinylpyrrolidinone . 6. The method of claim 5, wherein the drug is ketotifen fumarate. 7. A contact lens formed from a recognizable polymeric hydrogel matrix, said polymer hydrogel matrix which is formed of: a) a functionalized monomer or monomers synthesized or selected by identifying receptor sites or molecules associated with a target biological tissue to be treated with a drug, wherein the functionalized portions of the functionalized monomer or monomers are synthesized to be chemically and / or structurally or mimic the receptor sites or molecules that are associated with the biological mechanism of action of the drug; b) a drug; Y c) a crosslinking monomer; for use in dispensing the medication to a biological tissue. The contact lens of claim 7, wherein the drug is selected from the group consisting of an antibiotic, an antiinflammatory, an antihistamine, an antiviral agent, a cancer drug, an anesthetic, a cycloplegic, a mydriatic , a lubricating agent, a decongestant, a vasoconstrictor, an immunosuppressant, an immunomodulatory agent, an anti-glaucoma agent, an anti-infective agent and an alpha-adrenergic agonist. The contact lens of claim 7 or claim 8, wherein said use further comprises reloading the polymeric hydrogel matrix with the drug by soaking the polymer hydrogel matrix in an aqueous solution of the drug. The contact lens of any one of claims 7 to 9, wherein the drug is an antihistamine, wherein the functionalized monomers comprise acrylic acid, acrylamide and N-vinylpyrrolidinone. 11. The contact lens of claim 10, wherein the drug is ketotifen fumarate.