HK1166608B - Anionic oil-in-water emulsions containing prostaglandins and uses thereof - Google Patents

Description

Anionic oil-in-water emulsions containing prostaglandins and uses thereof

Technical Field

The present invention relates to prostaglandin containing anionic oil-in-water emulsions for topical administration of prostaglandins and in particular for the treatment of ocular disorders or diseases, preferably ocular disorders affecting the interior of the eye, in particular the anterior segment of the eye, including ocular hypertension and/or glaucoma, and for promoting eyelash growth and/or for the treatment of eyelash hypotrichosis. The anionic oil-in-water emulsion according to the invention further has the advantage of increasing the chemical stability of the prostaglandin.

Background

Glaucoma is a disease characterized by elevated intraocular pressure (IOP), which often results in damage to the optic nerve and visual field defects. Glaucoma, if left untreated, can eventually lead to blindness.

Prostaglandins (e.g. prostaglandin F)_2αAnd phenyl substituted analogs thereof) have been shown to be effective in lowering IOP in humans and animals. Indeed, they have been used in ophthalmic formulations to treat glaucoma. For example, latanoprost (latanoprost) is available in the form of topical ophthalmic solutions (eye drops) and is available under the trademark latanoprostAnd (7) selling.

In fact, latanoprost is a potent prostaglandin F_2αAnalogs that have been developed for the treatment of glaucoma. The chemical name is (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (3R) 3-hydroxy-5-phenylpentyl]-cyclopentyl group]-isopropyl-5-heptenoate,the molecular formula is C₂₆H₄₀O₅And the chemical structure is:

specifically, latanoprost is a lipophilic prodrug in which the carboxylic acid moiety in the alpha-chain is esterified to increase the bioavailability of the active drug in the eye. In addition, latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form, thus having biological activity.

Some ocular prostaglandins, such as bimatoprost (bimatoprost), latanoprost, or travoprost (travoprost), have also been described as promoting eyelash growth. The prostaglandins are therefore useful for the topical treatment of eyelash hypotrichosis.

A problem commonly encountered with prostaglandins is that they may be chemically unstable. In particular, latanoprost is known to be very sensitive to light and heat. In fact, both factors (i.e. light and heat) may have an effect on the stability of latanoprost by causing its hydrolysis and/or oxidation. Thus unopenedThe vials should be refrigerated in the dark at 2-8 ℃.

Therefore, there is a need for prostaglandin formulations that exhibit high prostaglandin chemical stability and high stability to light and heat, especially over long periods of time.

The applicants have conceived prostaglandin emulsions and found that emulsions are suitable vehicles for stabilizing prostaglandins (see, e.g., WO 2007/042262).

However, applicants have recognized that cationic emulsions containing cationic agents, preferably quaternary ammonium halides, may not be suitable for patients who are intolerant to this ingredient. This intolerance to quaternary amines leads to corneal and conjunctival lesions. These pathologies may be caused by dry eye, allergy, injury, cataract surgery, LASIK refractive surgery, chemical burns, trauma, irritation, bacterial infections, fungal infections or viral infections or side effects of some medications. Corneal or conjunctival disorders are local destruction of corneal, conjunctival or goblet cells. The lesions may be localized or diffuse and result in corneal erosion, punctate corneal lesions, epithelial defects, corneal ulceration, corneal scarring, corneal thinning, corneal perforation, keratitis, conjunctivitis, wounds, minor abrasions, and the like. These lesions are very harmful and very painful. Symptoms of these pathologies can be dryness, burning sensation and gritty eye irritation. Symptoms may also be described as itching, rubbing, stinging or fatigue of the eyes. Other symptoms are ocular pain, redness, distending pain (pullingsensing) and fundus pressure (pressure feeling). Damage to the surface of the eye increases discomfort and sensitivity to bright light. The applicant has therefore sought an emulsion free of cationic components. Although the applicants believe that the cationic component may play a role in stabilizing the prostaglandin, in the present invention it is demonstrated that, surprisingly, emulsions containing prostaglandin but no cationic agent are stable over a long period of time. The applicants have excluded cationic surfactants and turned the direction of research to nonionic surfactants. Again surprisingly, the use of a nonionic surfactant does produce an anionic emulsion. Without being bound by any theory, applicants believe that during the manufacturing process, the emulsion releases negatively charged components.

The invention therefore relates to an anionic emulsion made from starting components which are not negatively charged. According to one embodiment of the invention, the starting material for the manufacture of the present invention does not comprise any anionic surfactant.

The present invention provides a prostaglandin composition, preferably free of cationic ingredients, which exhibits high prostaglandin stability compared to commercial products, while being non-toxic, tolerated by patients with ocular surface lesions, and at least as effective as commercially available products.

Disclosure of Invention

One object of the present invention is a colloidal oil-in-water emulsion characterized in that it comprises:

-prostaglandin F_2α，

-an oil having an iodine value of 2 or less,

-a nonionic surfactant, and

-water, which is water,

wherein the non-ionic surfactant releases a negative charge during the manufacturing process,

the emulsion has a negative zeta potential of less than 10mV and the emulsion is free of polyvinyl alcohol.

According to one embodiment, the emulsion does not comprise any phospholipids.

According to another embodiment, the emulsion does not comprise a polyethoxylated castor oil derivative.

According to the invention, "colloidal" means that the emulsion comprises colloidal particles having a particle size of 1 μm or less dispersed in water, said colloidal particles having an oily core surrounded by an interfacial film. Typically, the oily core comprises a prostaglandin and an oil. Prostaglandins are lipophilic and therefore are understood to be substantially present in the oily core. Typically, the emulsion may contain other ingredients such as emollients (preferably glycerin) or pH modifiers (e.g. NaOH), penetrants and preservatives.

In the emulsion of the present invention, the colloidal particles have an average particle diameter of 1 μm or less, suitably 300nm or less, more suitably in the range of 100nm to 250 nm.

In one embodiment, the prostaglandin is prostaglandin F_2αA derivative, precursor, prodrug or analog thereof. Preferably, the emulsion comprises prostaglandin F_2αEster prodrugs, amide prodrugs or mixtures thereof. Ester prodrugs include C₁-C₄Alkyl estersProdrugs, e.g. methyl, ethyl, isopropyl or butyl esters, amide prodrugs including C₁-C₄Alkylamide prodrugs such as formamide, acetamide, isopropylamide or butyramide.

According to a particular embodiment, the prostaglandins F of the invention_2αSelected from latanoprost, isopropyl unoprostone (isoproyl unoprostone), travoprost, bimatoprost, tafluprost (tafluprost), or mixtures thereof; ester or amide prodrugs of latanoprost, isopropyl unoprostone, travoprost, bimatoprost, tafluprost; or mixtures thereof. Preferably, the emulsion according to the invention comprises latanoprost.

The prostaglandin content in the oily core of the emulsion according to the invention depends on prostaglandin F_2αThe nature and intended use of the composition. In a preferred embodiment of the invention, prostaglandin F_2αThe amount of (B) is comprised between 0.001 and 1% w/w, preferably between 0.002 and 0.3% w/w, and more preferably between 0.004 and 0.15% w/w, relative to the total weight of the emulsion.

In a particular embodiment, the prostaglandin may be combined with other anti-glaucoma active ingredients, such as dorzolamide (dorzolamide) or timolol (timolol).

In another embodiment, the emulsion is an ophthalmic emulsion comprising an effective amount of prostaglandin F_2αFor the treatment of ocular hypertension and/or glaucoma.

According to the invention, the oil is preferably chosen from saturated oils.

According to the invention, a "saturated oil" is an oil having an iodine value of less than or equal to 2, preferably less than 2, which means that said oil is substantially free of any molecules having hydrocarbon chains with double or triple bonds.

Iodine value may be measured, for example, according to the methods disclosed in the european pharmacopoeia monograph 2.5.4 or the us pharmacopoeia 401.

According to a particular embodiment of the invention, the oil is selected from the group consisting of oily fatty acids, oily fatty alcohols, fatty acid esters (e.g. isopropyl myristate, isopropyl palmitate), vegetable oils, animal oils, mineral oils (e.g. petrolatum, liquid paraffin), semi-synthetic oils (e.g. fractionated oils obtained from vegetable oils) or mixtures thereof.

According to the present invention, a "semi-synthetic oil" is prepared by chemical synthesis from a natural oil.

In particular, the oil according to the invention is a semi-synthetic oil obtained from fractionated coconut oil, kernel oil or babassu oil. More specifically, the oil is Medium Chain Triglycerides (MCT).

In fact, according to the european pharmacopoeia, Medium Chain Triglycerides (MCT) are described as non-volatile oils extracted from the hard, dry part of the endosperm of coconut (coco nucifera L.) by hydrolysis, fractionation of the obtained fatty acids and re-esterification. MCT consists of a mixture of short or medium chain triglycerides containing only fatty acids, not less than 95% of which are the saturated fatty acids caprylic and capric acid.

Furthermore, in addition to some animal products (e.g., milk fat) that may contain small amounts (up to 4%) of MCT, large amounts of MCT may also be found in nuclear and babassu oils.

In another embodiment of the invention, the pH of the emulsion is preferably between 4 and 7, in particular between 4.5 and 6.5, and more in particular between 5 and 6.

In a preferred embodiment of the invention, the amount of oil is not higher than 7% w/w, preferably between 0.5 and 5% w/w, and more preferably between 1 and 3% w/w, relative to the total weight of the emulsion.

Typically, nonionic surfactants that may be present in the emulsions of the present invention include alkyl polyethylene oxides, alkyl phenol polyethylene oxides, poloxamers (poloxamers), tyloxapol (tyloxapol), alkyl polyglucosides, fatty alcohols, cocamide MEA, cocamide DEA, sorbitan esters, polyoxyl stearates, polysorbates, or mixtures thereof.

In a preferred embodiment of the invention, the emulsion contains polysorbate, preferably polysorbate 80. According to one embodiment of the invention, the emulsion contains only one nonionic surfactant, preferably polysorbate 80. In another embodiment, the emulsion comprises an effective amount of prostaglandin F_2αPolysorbate 80, MCT, glycerol and water.

In another embodiment of the invention, the emulsion may further comprise an anionic surfactant, such as perfluorooctanoate, perfluorooctanesulfonate, alkyl sulfate, sodium lauryl ether sulfate, alkylbenzene sulfonate, soap or fatty acid salt or a mixture thereof.

Typically, the zwitterionic surfactant comprises dodecyl betaine, cocamidopropyl betaine, cocamidoamphoglycinate (cocoamphoglycinate), or mixtures thereof.

Typically, the surfactant according to the present invention comprises a hydrophilic surfactant (having a high HLB) and/or a lipophilic surfactant (having a low HLB) or a mixture thereof.

In a particular embodiment, the surfactant is selected from the group consisting of poloxamers, tyloxapol, polysorbates, sorbitan esters, polyoxyl stearates or mixtures thereof.

In another embodiment, the emulsion is free of any cationic agent, in particular cationic surfactants.

In another embodiment, the emulsion is free of water soluble polymers, in particular free of water soluble polymers selected from polyvinyl compounds, water soluble cellulose compounds or polysaccharides.

In certain embodiments, prostaglandin F is in emulsion_2αThe mass ratio/total of surfactants is between 0.01 and 5, or between 0.01 and 4, or between 0.01 and 3, or between 0.01 and 2, or between 0.01 and 1, or between 0.01 and 0.99, or between 0.02 and 0.08, or between 0.04 and 0.06, or about 0.05.

In one embodiment, the amount of surfactant comprises between 0.0005 and 1% w/w, preferably between 0.001 and 0.5% w/w, and more preferably between 0.01 and 0.5% w/w, relative to the total weight of the emulsion, provided that prostaglandin F is present in the emulsion_2αThe mass ratio/total of surfactants is between 0.01 and 5.

The emulsions according to the invention have a negative zeta potential. The negative zeta potential is preferably less than-10 mV (excluding-10 mV), preferably less than-15 mV, more preferably less than or equal to-20 mV.

It has long been recognized that zeta potential is an excellent index of the degree of interaction between colloidal particles, and measurements of zeta potential are commonly used to assess the stability of colloidal systems. The zeta potential measured in a particular system depends on the chemistry of the surface and the way the surface interacts with its surroundings.

Typically, the emulsions according to the invention are physically stable over a long period of time and maintain a negative zeta potential for up to two years at 25 ℃. The zeta potential of the surface of the emulsion droplet is determined by electrophoretic mobility in a device, such as a Malvern Zetasizer2000(Malvern Instruments, UK), equipped with suitable software and calibrated with the standard provided.

If necessary, the emulsion is diluted with double distilled water in order to obtain a scattering intensity that allows optimal particle detection. The sample count rate in heterodyne detection should be between 100 and 1000KCps (if heterodyne detection is used, the contribution of the reference beam should be deduced). Three measurements were carried out in succession at 25 ℃ using a constant voltage of 150 mV. The electrophoretic mobility was converted into a zeta potential value by the Smoluchowsky equation using the dielectric constant and viscosity of water. The measured value corresponds to the average of 3 values obtained.

In a particular embodiment, the emulsion of the invention does not contain any buffer.

According to the present invention, the emulsion remains physically stable during autoclaving. According to the invention, "autoclaving" is defined as sterilizing the product with steam under pressure by heating the product in an autoclave at elevated temperature (e.g. 100 to 200 ℃, preferably 121 ℃) for a prolonged period of time (e.g. 10 to 60 minutes, preferably 10 to 20 minutes) at a pressure of about 103kPa (15psi) above atmospheric pressure. The steam and pressure transfer sufficient heat to the organisms to kill them, thus sterilizing the product.

According to the invention, "stability" is defined as the degree to which a product retains the same properties and characteristics that it had at the time of manufacture, within specified limits and throughout storage and use (i.e. shelf life).

The purpose of stability testing is to provide evidence about the quality of a drug or drug product over an extended period of time, the product being affected by various environmental factors, such as temperature, humidity and light. The results may help provide proper storage conditions, retest periods, and shelf life.

While conventional stability studies do not assess those factors that ultimately affect the shelf life of a drug, these conventional studies are very time and cost effective. Thus, for example, to predict shelf life of pharmaceutical products, the pharmaceutical industry often uses "accelerated stability studies" (stress testing). These accelerated studies help understand the intrinsic stability mechanisms of the molecule of interest by determining degradation pathways and identifying possible degradation products. In these types of studies, the products are typically exposed to extreme conditions, such as temperatures of about 40 ℃ for about 6 months.

In the present invention, applicants have developed a "pressure test" during which the emulsion is exposed to a temperature of 80 ℃ for up to 14 days.

According to the invention, "good tolerability" means that the ratio of "therapeutic benefit" to "eye discomfort" is accepted by the patient, preferably similar to placebo or 0.9% NaCl solution.

Another object of the invention is a process for the manufacture of the emulsion described previously. The invention relates in particular to the production of emulsions having a negative zeta potential from starting materials which are free of anionic surfactants but contain nonionic surfactants which are capable of releasing negatively charged components during the production process.

The process of the invention uses as starting materials:

-prostaglandin F_2α，

-an oil having an iodine value of 2 or less,

-a nonionic surfactant, and

-water, which is water,

the method comprises preparing an oil phase by mixing the prostaglandin and the oil, preparing an aqueous phase by mixing the non-ionic surfactant and water, shear mixing the oil phase and the aqueous phase, adjusting the pH of the resulting emulsion, and optionally autoclaving the resulting emulsion.

According to a preferred embodiment, the process of the invention comprises the following steps:

-preparing an oily phase by mixing a prostaglandin (e.g. latanoprost) and a saturated oil (e.g. MCT);

-preparing an aqueous phase by mixing water soluble ingredients (such as glycerol and/or polysorbate 80) and purified water;

-combining the oil phase into the aqueous phase;

-rapidly heating the obtained crude emulsion, preferably at 75 ℃;

-reducing the size of the emulsion droplets by any suitable method known to the person skilled in the art, for example by shear mixing;

-cooling the emulsion using an ice bath, preferably to about 20 ℃;

-homogenizing the cooled emulsion;

-optionally adjusting the pH to physiological pH, e.g. by using NaOH or HCl;

preferably, sterilization is performed, more preferably by autoclaving.

The emulsions according to the invention are preferably intended for topical application to the surface of the eye or to hair, for example the eyelashes.

An object of the present invention is an anionic oil-in-water emulsion according to the present invention for use in a method for the treatment of ocular hypertension and/or for the treatment of glaucoma.

An object of the present invention is an anionic oil-in-water emulsion according to the present invention for use in a method of promoting eyelash growth or treating eyelash hypotrichosis.

An object of the present invention is an ophthalmic formulation comprising an anionic oil-in-water emulsion according to the invention, optionally in combination with an ophthalmically physiologically acceptable carrier. The formulation may be in the form of eye drops, eye ointments or eye gels.

It is an object of the present invention to improve the chemical stability of prostaglandins using the anionic oil-in-water emulsions according to the present invention.

One object of the present invention is a delivery device comprising an anionic oil-in-water emulsion according to the present invention.

Typically, the delivery device according to the invention is selected from the group comprising a lens, an eye patch, an implant, an insert.

The reader will appreciate further features and advantages of the invention upon reading the following non-limiting examples.

Drawings

FIG. 1: latanoprost free acid concentration in the ciliary body and cornea after administration of the emulsion of the invention.

Detailed Description

Examples

1. Preparation of anionic oil-in-water emulsions

The anionic oil-in-water emulsion according to the invention can be prepared by the following steps:

-preparing an oily phase by mixing prostaglandin (latanoprost) and saturated oil (MCT) at 50 ℃;

-preparing an aqueous phase by mixing glycerol, polysorbate 80 and purified water at 50 ℃;

-combining the oil phase into the aqueous phase;

-rapidly heating the obtained crude emulsion at 75 ℃;

-reducing the emulsion droplet size by any suitable method known to the skilled person, for example by shear mixing at 16000rpm for 5 minutes (Polytron PT6100, Kinematica, Switzerland);

-cooling the emulsion to about 20 ℃ using an ice bath;

homogenizing the cooled emulsion at 15000psi over 20 minutes (emulsisiflex C3, Avestin, Canada);

-pH adjustment with NaOH1M at pH 7;

-sterilizing the emulsion by autoclaving.

The composition of the emulsion is provided in table 1.

TABLE 1

MCT (Medium chain triglycerides)

qs: proper amount of

2. Stability test and comparative test

The stability of the emulsion of example 1 was evaluated under accelerated conditions "pressure test" (80 ℃, 14 days), while under the same "pressure test" conditions in the anionic emulsion (invention) andcomparative analysis was performed between them. Prostaglandin content was analyzed by HPLC-UV method in both tests.

The results are provided in table 2 (stability test) and table 3 (comparative test).

TABLE 2

The emulsions according to the present invention show a high stability after exposure to the stress test conditions (i.e. stress test) for a period of at least 14 days.

TABLE 3

At T0, emulsions (according to the invention) andthe concentration of prostaglandins in the composition is close to 0.005%. However, after exposure of both emulsions to the "stress test" (80 ℃, 14 days), it was observed that the concentration of prostaglandin in the emulsion (invention) remained unchanged, whereasThe concentration of prostaglandins in the medium is reduced by more than half.

3. Pharmacokinetic/pharmacodynamic study of the emulsions of Table 1

The emulsions of table 1 were administered to male and female new zealand white rabbits, and the following target tissues were assayed for the concentration of latanoate free acid at different time points (0.25, 0.5, 1, 4, 6 and 24 hours) after administration: conjunctiva, cornea, aqueous humor, and ciliary body. Tmax and AUC0.5-24h were calculated and are presented in Table 4 below. Latanoprost free acid is latanoprost hydrolyzed by esterase to its active form.

TABLE 4

Tmax represents the time to reach maximum concentration of latanoprost free acid.

Figure 1 (ciliary body and cornea) and the results presented above show that latanoprost free acid is present in high concentrations in the target tissues of the eye after administration of the emulsion. The concentration is known to be sufficient to allow Schlemm's canal (Schlemm's canal) to open and thus empty the aqueous humor, thereby lowering intraocular pressure.

Claims (12)

1. A colloidal oil-in-water emulsion comprising:

-prostaglandin F_2α，

-an oil with an iodine value of 2 or less, said oil being a medium chain triglyceride,

-a nonionic surfactant which is a polysorbate, and

-water, which is water,

wherein

The nonionic surfactant releases negative charges during the manufacturing process of the emulsion,

the emulsion has a negative zeta potential of less than-10 mV,

the amount of polysorbate is between 0.0005 and 1% w/w relative to the total weight of the emulsion,

wherein the amount of said oil is not higher than 7% w/w relative to the total weight of the emulsion,

and the emulsion is free of polyvinyl alcohol, the emulsion is free of cationic agents,

and the starting material is not negatively charged and the starting material does not comprise any anionic surfactant.

2. The colloidal oil-in-water emulsion according to claim 1, wherein the prostaglandin is selected from latanoprost (latanoprost), isopropyl unoprostone (isoproyl unoprostone), travoprost (travoprost), bimatoprost (bimatoprost), tafluprost (tafluprost); ester or amide prodrugs of latanoprost, isopropyl unoprostone, travoprost, bimatoprost, tafluprost; or mixtures thereof.

3. The colloidal oil-in-water emulsion according to claim 1, wherein the amount of prostaglandin is comprised between 0.001 and 1% w/w relative to the total weight of the emulsion.

4. The colloidal oil-in-water emulsion according to claim 2, wherein the amount of prostaglandin is comprised between 0.001 and 1% w/w relative to the total weight of the emulsion.

5. The colloidal oil-in-water emulsion according to claim 1, wherein the amount of prostaglandin is comprised between 0.002 and 0.3% w/w relative to the total weight of the emulsion.

6. The colloidal oil-in-water emulsion according to claim 2, wherein the amount of prostaglandin is comprised between 0.002 and 0.3% w/w relative to the total weight of the emulsion.

7. The colloidal oil-in-water emulsion according to claim 1, wherein the amount of prostaglandin is comprised between 0.004 and 0.15% w/w relative to the total weight of the emulsion.

8. The colloidal oil-in-water emulsion according to claim 2, wherein the amount of prostaglandin is comprised between 0.004 and 0.15% w/w relative to the total weight of the emulsion.

9. The colloidal oil-in-water emulsion according to any one of claims 1 to 8, wherein the emulsion does not contain any buffering agent.

10. The colloidal oil-in-water emulsion according to any one of claims 1 to 8 for use in the treatment of ocular hypertension and/or for the treatment of glaucoma.

11. The colloidal oil-in-water emulsion according to claim 9 for use in the treatment of ocular hypertension and/or for the treatment of glaucoma.

12. A process for the manufacture of the colloidal oil-in-water emulsion according to any one of claims 1 to 11, comprising as starting materials

-prostaglandin F_2α，

-not more than 7% w/w of an oil having an iodine value ≦ 2 for the total weight of the emulsion, said oil being a medium chain triglyceride,

-between 0.0005 and 1% w/w of a non-ionic surfactant which is a polysorbate, and

-water, which is water,

the method comprises preparing an oil phase by mixing the prostaglandin and the oil, preparing an aqueous phase by mixing the non-ionic surfactant and the water, shear mixing the oil phase and the aqueous phase, adjusting the pH of the resulting emulsion, and optionally autoclaving the resulting emulsion.