KR101099826B1 - Pharmaceutical liquid formulations of anti-allergic agents for intranasal delivery - Google Patents

Abstract

The present invention relates to a nasal administration liquid formulation containing an anti-allergic drug as an active ingredient and present in the form of a microemulsion or a temperature sensitive gel, wherein the nasal administration liquid formulation is easily administered to a patient having difficulty in oral administration. And can minimize side effects and systemic side effects in the gastrointestinal tract that may occur upon oral administration. In addition, drugs that require systemic absorption can increase bioavailability, and drugs that act on the nasal mucosa have the advantage of maximizing pharmacological action by delivering drugs directly near the drug action point.

Anti-allergic drugs, nasal administration, liquid preparations, mucoadhesion, bioavailability improvement

Description

Pharmaceutical liquid formulations of anti-allergic agents for intranasal delivery}

The present invention provides a nasal cavity containing an anti-allergic drug as an active ingredient, which can obtain a biological equivalent similar to that of oral preparations, improve the allergy treatment effect, and minimize side effects and systemic side effects in the gastrointestinal tract. It relates to a liquid preparation for administration.

Nasal administration has recently attracted attention as an alternative route of injection and oral administration for reasons of fast pharmacologic action time, relatively large absorption surface area, non-invasive methods, and avoidance of first-pass effects in the liver. However, attempts to overcome these shortcomings continue because there are disadvantages such as removal of drugs from mucosal epithelial tissue by mucus, relatively fast mucus replacement time, irritation and toxicity that may occur upon repeated administration.

Recently, various nasal delivery systems have been studied, including peptides and protein preparations with low bioavailability during oral administration, as well as cardiovascular drugs, central nervous system drugs, and inflammatory diseases. Research into direct administration of drugs for the treatment of respiratory diseases, including allergic rhinitis and asthma, directly into the nasal cavity.

Allergic rhinitis is a disease in which the nasal mucosa is hypersensitive to certain substances and is characterized by continuous sneezing, water-based nasal congestion, nasal obstruction. Other symptoms include pruritus of the eyes, larynx, loss of smell, headache, excessive tears, and fatigue. It often occurs from a young age, and if not properly treated, it can cause chronic sinusitis, nasal polyps, and otitis media. In case of allergic rhinitis, it is divided into seasonality and perenniality. Seasonality is usually caused by pollen of plants, and perenniality is mainly caused by dust, ticks, and fungi in the house.

Treatment of allergic rhinitis includes avoidance therapy, drug therapy (use of antihistamines, nasal decongestants, steroids, etc.), surgical therapies (harm patrol catheterization, nasal turbinate extraction, cryotherapy, etc.), immunotherapy (topical immunotherapy, systemic) Immunotherapy), ganglion block therapy, and the like. Drug therapy is the most convenient and efficient treatment method, such as antihistamines, corticosteroids, mucosal contractors, parasympathetic blockers, mast cell stabilizers, mucus inhibitors, nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs are used.

Conventional allergic rhinitis treatments are available in a variety of formulations, including oral, injectable, and nasal spray formulations. In the case of oral and injectable preparations, formulations that can be administered directly to the nasal cavity are being developed because systemic side effects may occur depending on the drug and symptoms and the therapeutic effect of the drug may be reduced.

However, conventional nasal preparations are mainly composed of simple liquid preparations, and are likely to flow down and be lost during administration. Therefore, there is a need for a formulation design to enhance the therapeutic effect by increasing the bioavailability of drugs as well as patient compliance.

Accordingly, an object of the present invention can increase medication compliance for patients suffering from oral administration of anti-allergic drugs including antihistamines and steroids, can reduce systemic side effects, and minimize foreign body sensation and irritation of powder formulations. It is to develop a liquid preparation for nasal administration.

In order to achieve the above object, the present invention provides a liquid formulation for nasal administration, characterized in that consisting of 0.1-5% by weight of anti-allergic drug, 2-10% by weight of oil, 20-70% by weight of surfactant and the remaining amount of water. do.

Anti-allergic drugs used in the present invention include an antihistamine selected from the group consisting of cetirizine, fexofenadine, azelastine, desloratadine, and tecastemizole; Steroids selected from the group consisting of budesonide, hydrocortisone and prednisolone; Anticholinergic agents selected from the group consisting of itratropium bromide, oxytropium bromide and tiotropium bromide; Napazoline, oxymethazolin and xylometazoline; And it may be any one selected from the group consisting of immunosuppressants selected from the group consisting of chromoline sodium, montelukast and nedocromyl.

In this case, when the anti-allergic drug is used out of the content range, it may not obtain an appropriate symptom-improving effect, or may cause unwanted side effects such as endocrine and immune system abnormalities. In addition, repeated use may cause toxicity to the nasal mucosa, which is the site of administration, and may also be economically costly for repeated administration.

The oil used in the present invention increases the solubility of the anti-allergic drug and increases the permeability of the drug through the mucosa, such oils include castor oil, soybean oil, cottonseed oil, corn oil (corn oil), palm oil, iso Propyl myristate, capriol 90, lauroglycol 90, liquid paraffin, oleic acid, ethyl oleate, dimethylacetamide, linoleoyl macrogolglycerides (Labrafil M 2125 CS) and oleoyl macrogolglycerides (Labrafil M 1944 CS) may be any one or two or more selected from the group consisting of. Preferably, lauroglycol 90 is used for fexofenadine hydrochloride and isopropyl myristate is used for budesonide.

The surfactant used in the present invention minimizes the interfacial tension between the aqueous phase and the oil phase, so that the two phases are mixed with each other, and increases the solubility of the drug and the permeability in the mucosa. / Capric glyceride (Labrasol ^® ), Olein polyglycerol (Plurol Oleique CC497) or Olein polyglycerol (Plurol Oleique CC497) / polyethylene glycol 400 is used.

Liquid preparation according to an embodiment of the present invention may be implemented in the form of a microemulsion. However, when the content range of the oil, surfactant, and water in the present invention is out of the range, the microemulsion may not be made.

The particle shape and size of the microemulsion according to the present invention is observed by Transmission Electron Microscopy (TEM) and preferably forms a spherical shape having an average diameter of 100 nm or less.

In addition, the liquid formulation may be implemented in the form of a temperature sensitive gel by additionally including an adhesive polymer. More preferably, the liquid formulation for nasal administration in the form of a temperature sensitive gel is 0.1-5% by weight of an antiallergic drug, 10-20% by weight of poloxamer, 0.1-5.0% by weight of a tacky polymer, 0.1-5.0% by weight of an absorption enhancer. And residual amount of water.

At this time, the adhesive polymer increases the time the temperature-sensitive gel according to the present invention stays on the mucosa and serves to enhance the absorption of the drug, such adhesive polymer, hyaluronic acid, chitosan, cellulose derivatives, polycarbopol (Polycarbopol ^® ), Any one or two or more selected from the group consisting of polyacrylic acid, collagen and gelatin, and more preferably chitosan or polycarbopol (Polycarbopol ^® ) are used.

In this case, when the adhesive polymer is used in a small amount out of the above content range when the temperature sensitive gel is prepared, the adhesive may not be sufficiently obtained, so that the absorption of the drug may not be enhanced, and when the excess is used, the viscosity is high, making the manufacturing difficult and slowing the release of the drug. It may also be toxic to mucosal epithelial cells.

In addition, the absorption enhancer plays a role of enhancing the nasal mucosal permeability of the drug, such absorption enhancer consisting of taurocholic acid, taurodeoxycholic acid, ursodeoxycholic acid, glycocholic acid and taurodihydrofusidic acid Any one or two or more bile salts selected from the group may be used, more preferably taurocholine acid.

In the temperature sensitive gel preparation of the present invention, a small amount of bile salt outside the above content range may not sufficiently enhance the permeation of the drug, and may cause toxicity to the nasal mucosal epithelial tissue when used in an excessive amount.

This temperature sensitive gel, for example, dissolves fexofenadine hydrochloride first in 10% by weight hydroxypropyl beta-cyclodextrin and then dissolves in poloxamer 407, the periodic agent. It may be prepared at a low temperature of about 4 ° C., and may be prepared by adding chitosan as an adhesive polymer and bile salt as an absorption accelerator.

The phase transition temperature of the temperature sensitive gel of the present invention can be measured by directly observing the gelation temperature according to the temperature rise, and the gelation temperature is about 30 ° C., which is considered to be a temperature that can be rapidly gelled upon intranasal spraying. .

The microemulsion according to the present invention may be formulated in a conventional pharmaceutical method by adding and mixing a pharmaceutically acceptable conventional adjuvant and the like, and preferably in the form of a nasal mucosal spray formulation by adding a conventional adjuvant. Can be. In order to increase other mucoadhesive properties, the polymer may be formulated by adding the polymer material.

The temperature sensitive gels of the present invention can also be formulated by conventional pharmaceutical methods with the addition of the corresponding polymeric materials to increase mucoadhesion and absorption promotion.

That is, the nasal administration liquid preparation according to the present invention may be added to preservatives such as benzalkonium chloride and phenylethyl alcohol, buffers, isotonic agents such as sodium chloride, flavoring agents such as menthol, eucapitol, campa and other excipients such as sweeteners. It may contain.

When the microemulsion and temperature sensitive gel according to the present invention are used as a liquid preparation for nasal administration, for example, the effective amount of fexofenadine hydrochloride is 20 to 120 mg / dose, preferably 30 to 60 mg / dose as fexofenadine. When the microemulsion of the present invention is used as a nasal administration liquid formulation, the effective amount of budesonide is 10 to 80 µg / dose, and preferably 32 to 64 µg / dose.

Nasal administration liquid preparations according to the present invention can increase medication compliance for patients who are difficult to oral administration during nasal spraying and can reduce systemic side effects. In addition, it is possible to minimize foreign body sensation and irritation of the powder formulation, and to expect a similar bioequivalence and symptom improvement effect as oral administration.

Hereinafter, the present invention will be described in more detail with reference to the following examples using fexofenadine hydrochloride and budesonide as anti-allergic drugs. However, the present invention is not limited by these examples.

Examples 1 to 4 Preparation of Microemulsions

A pseudo-ternary phase diagram was created using the dropwise addition of water, and a microemulsion was prepared by diluting the oil and the surfactant / cosurfactant with water. The solubility of fexofenadine hydrochloride in oils and surfactants was measured prior to microemulsion preparation, and monolauric acid propylene glycol 90 (Lauroglycol 90), PEG-8 caprylic / capric glyceride (Labrasol ^® ), olein poly Glycerol (Plurol Oleique CC497) / polyethylene glycol 400 were selected as oils, surfactants, and cosurfactants, respectively.

In the case of the microemulsion containing budesonide, the most soluble substance was selected after measuring the solubility in various oils and surfactants. For microemulsions containing budesonide, isopropyl myristate, PEG-8 caprylic / capric glyceride (Labrasol ^® ), oleic polyglycerol (Plurol Oleique CC497) / polyethylene glycol 400 Were prepared as oils, surfactants, and cosurfactants, respectively.

1A and 1B show a pseudo-ternary phase diagram of a microemulsion containing fexofenadine hydrochloride, and FIGS. 2A and 2B show a pseudo-ternary phase diagram of a microemulsion containing budesonide.

Example Main drug oil
(Weight / weight,%) Surfactants
(Weight / weight,%) Cosurfactant
(Weight / weight,%) Surfactants/
Cosurfactant Ratio One Fexofenadine hydrochloride
(10mg / ml) Lauroglycol 90
(4%) Labrasol ^®
(26%) Plurol Oleique CC497 (9%) 3: 1 2 Plurol Oleique CC497 / PEG400 (4.5% / 4.5%) 3 Budesonide (2.0mg / ml) Isopropyl myristate
(5%) Labrasol ^®
(33%) Plurol Oleique CC497 (16%) 2: 1 4 Plurol Oleique CC497 / PEG400 (8% / 8%)

To prepare a microemulsion formulation consisting of the components and the proportions as shown in Table 1 above.

<Examples 5 to 10> Preparation of temperature sensitive gel

Poloxamer based temperature sensitive gels were prepared by mixing at 4 ° C. Fexofenadine hydrochloride is dissolved in 10% (weight / volume ratio) of hydroxypropyl-beta-cyclodextrin (HP-β-CD) and then mixed with 17% (weight / volume ratio) of poloxamer 407 to add chitosan and other polymeric substances. Was prepared (see Table 2). Chitosan was added after dissolving in 1% acetic acid solution. Store at 4 ° C. for 24 hours to obtain a clear poloxamer solution. Table 2 shows the components and the ratio of components.

Example Concentration of fexofenadine hydrochloride (mg / ml) Poloxamer 407 concentration (%, w / v) Chitosan concentration
(%, w / v) Chlorinated Taurocholate (%, w / v) 5 10 - - - 6 10 17 - - 7 10 17 0.1 - 8 10 17 0.1 0.1 9 10 17 0.3 - 10 10 17 0.3 0.1

Experimental Example 1 Measurement of Physicochemical Properties of Microemulsion

The solubility, diameter, and viscosity of the microemulsion particles were measured to examine the physicochemical properties. The solubility of each drug was quantitatively determined by dissolving the drug after preparing the microemulsion.

In Examples 1 and 2, the solubility of fexofenadine chloride was increased by 14.4 and 9.6 times, respectively, and in Examples 3 and 4, it was 162.5 and 137.8 times higher than the solubility of budesonide in water, respectively.

Particle diameter was measured using a particle sizer (Nicomp 370 submicron particle sizer, Particle sizing system, Santa Barbara, CA) and in Examples 1 to 4 have a diameter of less than 100 nm.

The viscosity of the microemulsion was measured using a viscometer (DV-E viscometer, Brookfield, USA), and Examples 1 to 4 had a viscosity of about 100 cps.

Example Solubility of the main drug (mg / ml) Diameter (nm) Viscosity (cp) One 21.72 ± 0.25 97.83 ± 1.45 103 ± 6 2 14.43 ± 0.15 30.37 ± 0.95 61 ± 1 3 6.50 ± 0.15 83.47 ± 2.02 78 ± 1 4 5.51 ± 0.22 74.27 ± 2.12 67 ± 6

Experimental Example 2 Observation of Morphological Shape of Microemulsion

The morphology of the microemulsion was observed by transmission electron microscopy (Carl Zeiss, Germany). 3A to 3D show the particle forms of Examples 1 to 4. The particle size was spherical particles of 100 nm or less, similar to the size measured through a particle counter.

Experimental Example 3 Measurement and Evaluation of Blood Level of Drug in Nasal Administration of Microemulsion Formulation in Animal Model

We evaluated the in vivo kinetics of the drug, including blood concentrations of the drug, by administering fexofenadine hydrochloride powder, formulation, and solution to the male Spraque-Dawley rat. Examples 1 and 2, fexofenadine hydrochloride was administered nasal at a dose of 1 mg / kg, aqueous solution of fexofenadine hydrochloride was administered intravenously at a dose of 1 mg / kg, orally administered at a dose of 10 mg / kg. Only plasma was isolated and deproteinized by addition of acetonitrile containing an internal standard (terbinafine). After centrifugation, the supernatant was collected and volatilized with nitrogen gas, and the mobile phase was added and quantitatively analyzed by mass spectrometry (LC-MS / MS).

Blood concentration profiles of the drugs are shown in FIGS. 4A and 4B. Table 4 below describes the intracorporeal kinetics of the drug upon intravenous, oral and nasal administration. According to Table 4, the nasal administration of Examples 1 and 2 was faster than the oral administration, the time for the maximum blood drug concentration appeared, the half-life was also reduced. In comparison, the bioavailability was about 10 times higher.

In other words, it has been shown that nasal administration of microemulsions can increase the rate and rate of absorption of the drug. Therefore, the microemulsion formulation prepared in the present invention may be applied to the rapid absorption and maximization of efficacy of other anti-allergic drugs.

Volume
(mg / kg) Maximum blood
Drug concentration
(ng / ml) Maximum blood
Drug concentration
Measuring time
(min) Half-life
(min) Blood concentration
Curve
Area / capacity
(ng / ml * min) Biological
Utilization
(%) Intravenous One － － 100.46 ± 8.74 56480.91 ± 13358.84 － Oral administration 10 139.56 ± 50.21 60 219.52 ± 20.16 3729.72 ± 524.20 6.60 ± 0.65 Nasal administration
(Example 1) One 728.19 ± 31.73 5 87.78 ± 21.16 35188.25 ± 303.77 62.30 ± 0.54 ^** Nasal administration
(Example 2) One 1026.76 ± 95.25 5 95.69 ± 17.70 38789.87 ± 3164.45 68.68 ± 5.60 ^** Nasal administration
(powder) One 302.16 ± 25.17 10 91.51 ± 17.44 23887.62 ± 264.30 42.29 ± 0.47

<Experiment 4> Investigation of the viscosity characteristics of the temperature sensitive gel

Phase transition points were measured to observe the phase transition phenomenon according to the temperature change of Examples 5 to 10. The gelation temperature was 1ml of the formulation in a test tube and immersed in a temperature controlled water bath and then gradually increased the temperature was measured the temperature to become a gel. The gelation temperature was set at a time when the experimental tube was not tilted at 90 °. According to Table 5 it can be seen that the gelation temperature increases little by little to the added chitosan concentration.

Phase transition temperature (mean ± standard deviation) (℃) Example 6 29.9 ± 0.10 Example 7 30.3 ± 0.05 ^* Example 9 30.5 ± 0.15 ^*

Experimental Example 5 Experiment of Drug Transmission in Human Nasal Mucosal Membrane Model.

Human nasal mucosal tissue epithelial cells were cultured in transwell monolayer membrane by Air-Liquid Interface (ALI) culture method and drug permeability was measured from the formulation. In the permeation experiment, the formulation was added to the apical side of the transwell, the sample was taken from the basolateral side, and the concentration of the permeated drug in the sample was quantitatively analyzed using liquid chromatography.

As a result of the quantitative analysis, the higher the content of chitosan, the higher the permeability of the drug, and when sodium taurocholate was added in addition to the chitosan, the higher the permeability of the drug (Fig. 5).

Experimental Example 6 Evaluation of In vivo Kinetics of Drugs in Nasal Administration of Gel in Animal Models

A solution containing fexofenadine hydrochloride, Allegra tablets, and a temperature sensitive gel containing fexofenadine hydrochloride were administered intravenously, orally, and nasal respectively. Blood was drawn from the rabbit's ear artery at regular intervals after administration and deproteinized by adding acetonitrile containing an internal standard (propranolol). After centrifugation, the supernatant was volatilized with nitrogen gas, a mobile phase was added, and quantitatively analyzed using a mass spectrometer.

As a result, the pharmacokinetic values of the drugs could be calculated as shown in Table 6. In the nasal dosage form, the time to peak blood concentration was faster and bioavailability increased up to 2.7 times compared to oral administration.

Route of administration Peak blood concentration (ng / ml) Peak blood expression time (min) Half-life
 (min) Area under the blood concentration curve / dose
(ng / ml * min) Bioavailability (%) Intravenous administration (solution) 1047 ± 123.3 - 23.79 ± 2.115 43490 ± 9515 - Oral Administration (Allegra Tablets) 450.2 ± 119.0 30.00 117.6 ± 27.51 8332 ± 2002 19.16 ± 4.603 Nasal Administration (Example 5) 11.70 ± 1.319 10.00 66.25 ± 17.78 1450 ± 392.6 3.334 ± 0.903 Nasal Administration (Example 7) 52.96 ± 9.427 30.00 91.69 ± 31.30 11840 ± 741.8 27.22 ± 1.706 Nasal Administration (Example 9) 78.25 ± 21.25 15.00 247.7 ± 91.60 22220 ± 1017 51.09 ± 2.338

1A and 1B show a pseudo phase diagram according to one embodiment (Examples 1 and 2),

2A and 2B show pseudo phase diagrams according to one embodiment (Examples 3 and 4),

3A to 3D are views of one embodiment (Examples 1 to 4) observed with a transmission electron microscope,

Figure 4a shows the blood drug concentration over time after intravenous and oral administration of fexofenadine hydrochloride solution in white paper,

Figure 4b shows the blood drug concentration over time nasal administration of one embodiment (Examples 1, 2),

Figure 5 shows the amount of permeation of monolayer epithelial cell monolayer after the addition of one embodiment (Example 6, 7, 8, 9, 10) to human nasal epithelial cell monolayer over time.

Claims (7)

0.15% by weight fexofenadine, 10-20% by weight poloxamer, 0.1-5.0% by weight chitosan, 0.1-5.0% by weight taurocholine acid, 10% by weight hydroxypropyl-beta-cyclodextrin (HP-ß-CD) And a residual amount of water. delete delete delete delete The liquid formulation for nasal administration according to claim 1, wherein the liquid formulation is a temperature sensitive gel. delete

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