HK1075001B - Use of synthetic inorganic nanoparticles as carriers for ophthalmic and otic drugs - Google Patents

Description

Use of synthetic inorganic nanoparticles as carriers for ophthalmic and otic medicaments

Background

The present invention relates to ophthalmic and otic drug delivery, and in particular, the present invention relates to the use of synthetic inorganic nanoparticles as inert carriers in ophthalmic and otic drugs and the topical application of such pharmaceutical compositions based on the present invention to the eye and ear.

Many different types of materials have been used as vehicles for applying ophthalmic agents to the eye, for example, U.S. patent 4271143, which reports the use of carboxyvinyl polymers to achieve this. Many other organic polymers are also used as ophthalmic drug carriers.

The use of nanoparticles formed from synthetic or natural polymers in ophthalmic compositions has been disclosed in a number of scientific publications, for example:

kreuter, J. "nanoparticles"A colloidal drug delivery system comprising a delivery system for a drug,edited by Jork Kreuter, Marcel Dekker, New York (USA), p 219, Chapter 5 (1994);

gurny, R. "treatment of the eye with nanoparticles"Polymeric nanoparticles and microspheres BodyP.guiot and p.couverur editors, Boca Raton, florida (usa): CRC Press, page 127 (1986);

gurny, R. "preliminary discussion of prolonged active drug delivery systems in the treatment of glaucoma"Pharm Acta Helv.Vol.56, page 130 (1981);

zimmer et al, "use of microspheres and nanoparticles in ocular delivery systems"High-grade medicine Overview of material deliveryVol.16, No. 1, pages 61-73 (1995);

galvo et al, "comparison of in vitro evaluation of some micellar systems such as nanoparticles, nanocapsules and nanomicroemulsions as carriers for ophthalmic applications",J Pharm Scivol 85, 5 th, page 530 and 536 (1996, 5 months).

The nanoparticles used in the present invention are not synthetic or natural polymers as described in the publications cited above, and the present invention relates to the use of inorganic nanoparticles. Nanoparticles useful in the present invention include, for example, water swellable clay materials, and an overview of the chemical and physical properties of some of the related clays can be found below.

Giese, r.f. and van Oss c.j., "colloid and surface properties of clays and related minerals", a.t. hubbard, Marcel Dekker inc. volume 105.

The preferred nanoparticles are synthetic smectite clays prepared from simple silicates, and the following publications will indicate background on the use of synthetic clay nanoparticles in pharmaceutical compositions:

Plaizoer-Vercammen, "Laponite XLG, a rheological property of synthetic pure hectorite"Phamazie，Volume 47, page 856 (1992);

grandolini et al, "hydrotalcite-like anionic clay intercalating anti-inflammatory compounds: intercalation and in vitro Release of ibuprofen "International Journal of Pharmaceutics，Vol 220, periods 1-2, pages 23-32 (6/4/2001);

U.S. Pat. No. 5585108(Ruddy et al) entitled "preparation of an oral gastrointestinal therapeutic agent and a pharmaceutically acceptable clay";

U.S. Pat. No. 6177480B1(Tsuzuki et al) describes synthetic clay materials (e.g., Laponite)^TM) As a wetting agent for contact lenses to aid surfactants in removing lipid deposits from the lenses;

U.S. patent 6015816(Kostyniak et al) describes an improved method of micellar particles of, for example, smectite clay minerals, as ligand agents with antibacterial activity to control bacterial growth on materials;

U.S. Pat. No. 6177480(Tsuzuki et al) describes synthetic clay materials (e.g., Laponite)^TM) As contact lensesThe wetting agent helps the surfactant remove lipid deposits from the lens.

Summary of The Invention

The use of nanoparticles based on inorganic materials according to the invention for the formulation of ophthalmic and otic pharmaceutical compositions, in particular such compositions being suitable for topical tissue application to the eye and the ear. The nanoparticles are useful as chemically inert carriers or reservoirs for ophthalmic or otic medicaments and as part of ophthalmic or otic compositions.

The present invention is believed to be superior to the current delivery of ophthalmic drugs using organic polymers. For example, the inorganic nanoparticles used in the present invention are particularly suitable as drug delivery agents in situations where controlled release of the drug is desired. The ability of the microparticles to provide a high surface area and to disperse well in an aqueous medium as a transparent gel or solution allows the microparticles to provide advantages over existing delivery agents.

It has now been found that nanoparticles can be well dispersed and remain as a clear solution in very low concentration aqueous solutions. Due to the small size of the nanoparticles, the compositions of the present invention can remain clear and haze free, which is important for ophthalmic compositions. It has also been found that the microparticles can serve as a carrier for ophthalmic and otic medicaments without affecting the antimicrobial activity of the antimicrobial preservatives contained in the composition.

In addition to being an inert carrier for ophthalmic and otic drugs, the inorganic nanoparticles provide excellent rheological properties to the compositions of the present invention.

Detailed description of the invention

The nanoparticles applied in the present invention are inorganic substances. The particles have colloidal dimensions, large surface areas and very high ion exchange capacity. The particles are generally referred to hereinafter as inorganic nanoparticles. It is preferred to use synthetic inorganic nanoparticles.

The inorganic nanoparticles useful in the present invention are preferably less than 100 nanometers ("nm") in particle size, but greater than 1 nm, with a standard deviation of distribution of no more than 10%, and the shape of the nanoparticles is not limited to spherical, but may be disk, cubic, ellipsoidal or other particulate forms. The surface area of the particles is 30-1000 square meters per gram (m)²Per g) and an overall negative surface charge at a pH in the range of 6.0 to 7.8.

The inorganic nanoparticles used in the present invention may also be surface modified depending on the particular shape of the composition involved and the stability desired. Different types of nanoparticles may be combined to optimize the properties of the formulation.

The inorganic nanoparticles used in the present invention are preferably made of clay swellable in aqueous solutions. Such clays are referred to herein as hydrated. Synthetic hydrated clay nanoparticles are preferred because they are commercially available, pure, and well defined in terms of chemical composition and physical properties of these materials. In addition, synthetic clay nanoparticles are easier to formulate and form into colorless and transparent gels than inorganic nanoparticles formed from naturally occurring clays.

Particularly useful synthetic inorganic nanoparticles include those commercially available under the trade name Laponite(Southern Clay Products, Gonzales, Texas, USA). Laponite (Laponite)Is a layered hydrous magnesium silicate prepared from simple silicates. The disclosures of Laponite are available from the following publicationsIntroduction of physical properties and functions of (a): laponite Technical Bulletin, "Laponite-synthetic layerdsilicate-ics chemistry, structure and relationship to natural systems" L204/01g, whichHis synthetic magnesium aluminum silicate is also commercially available under the trade name OPTIELSH(Sud-Chemie，Louisville，Kentucky)。

Inorganic nanoparticles formed from naturally occurring hydrated clays can be used alone or in combination with synthetic clays. Suitable naturally occurring clays are, for example, alite, beidellite, bentonite, hectorite, kaolinite, magadite, montmorillonite, nontronite, saponite, sauconite, stevensite and volkonskoite.

The following publications may see further details regarding the physical properties of various types of clay nanoparticles and the usefulness of these materials as ion exchange materials, viscosity modifiers, and film formers:

gieseking, j.e. "cation exchange mechanism in clay minerals of the montmorillonite-beidellite-chlorite class",Soil Sciencevolume 47, pages 1-14 (1939);

the ng, b.k.g., the "formation and properties of clay polymer complexes", Elsevier, Amsterdam, (1979);

van Olphen, "clay colloid chemistry", Krieger publishing company, Florida, Second Edition (1991).

Examples of other inorganic nanoparticle materials that may be substituted for or combined with the clay nanoparticles as described above include: zeolites, hydrotalcites, silica, alumina, ceria, titania, and zinc oxide. Nanosized silica particles such as Nalco supplied by Nalco115 and 1140, and NaAcol of EKA chemical CoThe stages can be applied well. Mineral oxides based on other metalsAnd are also commercially available. For example, mineral oxides (e.g., alumina, ceria, titania, and zinc oxide) are available from Nanophase Technologies (Romeoville, Illinois, USA) under the trademark "Nano Tek"has a definite diameter of nanometers.

As mentioned above, the above-mentioned inorganic nanoparticles have been found to be very useful as carriers for ophthalmic and otic drug molecules and other components of ophthalmic and otic compositions. The present invention employs nanoparticles as carriers for various types of pharmaceutically active agents, such as agents for controlling intraocular pressure and treating glaucoma, neuroprotective agents, anti-allergic agents, anti-infective agents, anti-inflammatory agents, mucus secretagogues (mucosecretogogues), angiostatic steroids, pain relievers, congestion relievers or astringents, and the like.

Pharmaceutically active agents included in the compositions of the present invention and administered by the methods of the present invention include, but are not limited to, those: anti-glaucoma agents such as apronidine, brimonidine, betaxolol, timolol, pilocarpine, carbonic anhydrase inhibitors, prostaglandins, and 5-hydroxytryptamine; (ii) a dopamine antagonist; anti-infective agents such as moxidectin (moxifloxacin), gatifloxacin (gatifloxacin), levofloxacin, cyprocidin and tobramycin; non-steroidal and steroidal anti-inflammatory drugs such as rimexolone, dexamethasone, prednisolone, fluorometholone, lotoprenol, naproxen, diclofenac, suprofen, and ketorolac; a protein; growth factors, such as epidermal growth factor; mucus secretagogues, such as 15-HETE; neuroprotective agents, angiostatic steroids such as anecortave (anecortave) acetate; antihistamines, such as emedastine (emadine); mast cell stabilizers such as olopatadine (olopatadine) and immunomodulators such as cyclosporine.

The concentration of inorganic nanoparticles used in a particular ophthalmic or otic composition of the present invention will depend on the physical form of the composition (e.g., solution, dispersion, suspension, or gel) and other factors known in the art.The optimal concentration of nanoparticles for a particular formulation can be determined by routine experimentation, based on the description and the discussion herein. As a result of selected experiments, the desired concentration varies considerably between different formulations, generally in the range of 0.000001-10 w/v%, preferably 0.1-10 w/v%. Dispersed smectite clay nanoparticles (e.g., Laponite)) The concentration in the composition of the invention may vary considerably from one formulation to another but is generally in the range of 0.1-1 w/v%, preferably 0.3-0.5 w/v%.

It has been found that the inorganic nanoparticles as described above can be well dispersed in low concentration aqueous buffered solutions at physiological pH, maintaining a clear solution, dispersion or gel. At concentrations up to 10 w/v%, the inorganic nanoparticles form transparent, colorless, low-viscosity dispersions. However, if combined with appropriate salts and other excipients, the nanoparticles form transparent gels with high shear thinning and thixotropy. Particularly, at concentrations exceeding 0.5 w/v%, the microparticles will become transparent gels under appropriate electrolyte conditions, exhibiting lubricity, film formation and viscoelasticity.

The electrolyte conditions under which such a gel is to be formed will depend somewhat on the type of inorganic nanoparticle selected, the concentration used, the type of buffer or excipient, and other factors known in the art. The best electrolyte conditions are to use very low levels of 1: 1 electrolyte (such as sodium chloride). The desired concentration of the gel composition of the present invention can be readily obtained by routine experimentation with each formulation. But generally the amount of electrolyte required is in the range of 0.01 to 0.1 w/v%.

While the aqueous ophthalmic and otic compositions incorporating inorganic nanoparticles described herein have significant rheological changes, the compositions of the present invention typically have viscosities several orders of magnitude higher than the same compositions without the synthetic inorganic nanoparticles. The compositions of the present invention are preferably subjected to high shearHas a viscosity of less than 5.0mPa sec at rate. More particularly, the compositions of the present invention have shear rates in excess of 25sec^-1Has a newtonian plateau viscosity of less than 5.0mPa sec, most preferably the viscosity range is 0.1-1mPa sec.

The altered rheological properties provided by the inorganic nanoparticles as discussed above are used to extend the shelf life of the compositions of the present invention in the eye or ear, or to improve the flow characteristics of the compositions.

The ophthalmic and otic compositions according to the present invention may contain various auxiliary substances, such as buffers and tonicity adjusting agents, in addition to the above-mentioned synthetic inorganic nanoparticles and pharmaceutically active agents. Ophthalmic and otic compositions according to the present invention are generally formulated as sterile aqueous solutions, suspensions, dispersions or gels. The compositions must be formulated to be compatible with the tissues of the eye and ear. The osmolality of the ophthalmic solutions, suspensions and dispersions according to the invention is generally 200 to 400 milliosmol/kg water. All these compositions have a physiologically acceptable pH value.

Ophthalmic and otic compositions packaged as multi-dose products according to the present invention may contain one or more ophthalmically acceptable insecticides in an amount effective to avoid contamination by microorganisms such as bacteria and fungi. Pesticides used for this purpose are known as antimicrobial preservatives.

The invention is not limited to pesticides as antimicrobial preservatives. Preferred insecticides include: chlorhexidine, polyhexamethylene biguanide polymer (pHMB), polyquaternium-1 and aminobiguanide, described in U.S. patent application Ser. No. 09/581952 and corresponding International publication number (PCT), WO99/32158, the entire contents of which are incorporated herein by reference, preferably with the use of surface active insecticides.

Preferred antimicrobial agents are polyquaternium-1 and aminobiguanides, described in U.S. patent application Ser. No. 09/581952 and corresponding International publication number (PCT), WO99/32158, with the most preferred aminobiguanide described in U.S. patent application Ser. No. 09/581952, corresponding to PCT publication "Compound I", having the structure:

structural formula (I)

This compound is hereinafter denoted by AL 8496.

The level of antimicrobial activity required to prevent microbial contamination of ophthalmic or otic drugs is known in the art based on personal experience and official published standards, such as those set forth in the U.S. pharmacopoeia and similar regulations in other countries. The amount of antimicrobial preservative used for this purpose is referred to herein as the "effective amount".

The composition may also contain one or more ingredients to enhance the antimicrobial activity of the composition, e.g., borate/polyol complexes (e.g., boric acid/propylene glycol) as described in U.S. patent 6143799 (Choghan et al); small molecular weight amino alcohols (e.g., AMP) as described in U.S. patent 6319464B2 (asghanian); or a small molecular weight amino acid (e.g., glycine) as described in U.S. Pat. No. 5741817 (Choghan et al). The entire contents of the patents identified above are incorporated into this application by reference. The ingredients cited above may be used alone or in combination with an antimicrobial agent such as polyquaternium-1.

The compositions of the present invention are further described in terms of representative formulations as described in the following examples.

Examples

The following table provides examples of ophthalmic formulations containing rimexolone. The composition can be used for treating ocular inflammation. All concentrations in the table are expressed as weight/volume percentages.

Note: measured in an uncontrolled manner at room temperature using a Brookfield DVIII-ULA rotor.

Claims (8)

1. Use of synthetic inorganic nanoparticles as a carrier in ophthalmic or otic medicaments, wherein the nanoparticles are formed from synthetic aqueous clay and have: (a) the particle size is less than 100 nm but more than 1 nm, and the standard error of distribution is not more than 10%; (b) the surface area is in the range of 30 to 1000m²(ii)/g; and (c) a generally negative surface charge at a pH of between 6.0 and 7.8; and the concentration of the nanoparticles in the composition is 0.000001 to 10 w/v%.

2. Use according to claim 1, wherein the nanoparticles are present in the composition in a concentration of 0.1 to 10 w/v%.

3. Use according to claim 1, wherein the synthetic aqueous clay is a smectite clay.

4. Use according to claim 1 or 2, wherein the nanoparticles are selected from zeolites, hydrotalcites, silica, alumina, ceria, titania and zinc oxide.

5. An ophthalmic or otic pharmaceutical composition comprising a therapeutically effective amount of an ophthalmic or otic drug and an amount of synthetic inorganic nanoparticles sufficient to carry the drug, wherein the nanoparticles are formed from a synthetic aqueous clay and have: (a) the particle size is less than 100 nm but more than 1 nm, and the standard error of distribution is not more than 10%; (b) the surface area is in the range of 30 to 1000m²(ii)/g; and (c) a generally negative surface charge at a pH of between 6.0 and 7.8; and the concentration of the nanoparticles in the composition is 0.000001 to 10 w/v%.

6. The pharmaceutical composition of claim 5, wherein the concentration of the nanoparticles in the composition is from 0.1 to 10 w/v%.

7. The composition of claim 5 wherein the synthetic aqueous clay is a smectite clay.

8. A composition according to claim 5 or 6, wherein the nanoparticles are selected from the group consisting of zeolites, hydrotalcites, silicas, aluminas, cerias, titanias and zinc oxides.