KR100910848B1 - Microsphere for nasal spray comprising drug for treating allergic rhinitis and preparation method thereof - Google Patents

Abstract

The present invention relates to a nasal spray microspheres containing an antihistamine drug as an active ingredient and a method for preparing the same, including 10-20% by weight of an allergic rhinitis drug, 60-80% by weight of a tacky polymer, release The microsphere of the present invention composed of 1-10% by weight of the control agent and 1-15% by weight of the bile salts can easily administer the drug to patients who have a bitter taste masking of allergic rhinitis treatment drugs including antihistamines and have difficulty in oral administration. It can be used as a nasal nebulizer because the bioequivalence similar to that obtained in oral preparations for treating allergic rhinitis, including at least pharmacokinetic parameters, and at least conventional antihistamines, can be used as a nasal spray.

Antihistamines, allergic rhinitis, nasal spray, microspheres, bile salts

Description

Microsphere for nasal spray containing drug for treating allergic rhinitis and preparation method including allergic rhinitis treatment drug as active ingredient

The present invention is directed to a nasal spray microsphere consisting of 10-20% by weight of an allergic rhinitis therapeutic drug, 60-80% by weight of adhesive polymer, 1-10% by weight of release controlling agent and 1-15% by weight of bile salts and a method for preparing the same. It is about.

Allergic rhinitis is caused by allergens such as pollen, dust, fungus or animal hair, which can cause sneezing, itching, stuffy nose, runny nose, etc. Symptoms are divided into perennial allergic rhinitis, which occurs during two to three hours a day or more than nine months of the year by indoor antigens such as hay fever, seasonal allergic rhinitis called hay fever, house dust, and ticks.

When allergens that cause allergic rhinitis reach the inside of the nose, it stimulates blood vessels or secretory glands under the nasal mucosa, and a lot of runny nose comes out, and it is sneezing due to nerve reflection, sneezing, and to reduce inhalation of foreign substances from the outside Is clogged with effort.

Treatments for allergic rhinitis include avoidance therapy, drug therapy, surgical therapy, and specific immunotherapy. Among these drugs, antihistamines, corticosteroids, mucosal contractors, parasympathetic blockers, There are many types of drugs, such as mast cell stabilizers, mucus inhibitors, nonsteroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, etc. Also, if you have nasal congestion, use a nasal decongestant to calm it down and, in severe cases, steroids.

Some of these drugs, including antihistamines such as fexofenadine, are mainly marketed in the form of oral tablets or capsules, and have been very active through oral administration to date, the application of fexofenadine in patients for whom oral administration is not suitable. There was a limit to.

In particular, there is no preferred fexofenadine containing formulation for patients suffering from swallowing or for taking medication without liquid. Therefore, there is a great need for the development of a drug that is free from the bitter taste of an allergic rhinitis treatment drug such as fexofenadine and the like, so as to accelerate absorption and increase bioavailability to more efficiently express the efficacy.

Nasal mucosa has a wide absorption area and the absorption of drugs occurs quickly, so the effect of expression is fast. In particular, unlike oral administration does not go through the first pass effect in the liver shows a high bioavailability and has the advantage of increasing the patient's compliance.

Accordingly, the present inventors can easily administer the drug to a patient who has a bitterness masking ability of an allergic rhinitis treatment drug including an antihistamine and has difficulty in oral administration, and has a pharmacokinetic parameter, at least a conventional antihistamine treatment drug of an allergic rhinitis treatment agent. The present invention has been completed by developing microspheres for nasal sprays that can achieve biological equivalence similar to that obtained in oral formulations.

Accordingly, an object of the present invention is to provide a nasal spray microsphere composed of an antihistamine drug, an allergic rhinitis therapeutic drug, an adhesive polymer, a release controlling agent and a bile salt and a method for preparing the same.

Another object of the present invention is to provide a nasal spray comprising a microsphere consisting of an antihistamine treatment drug, an adhesive polymer, a release controlling agent and a bile salt, and a pharmaceutically acceptable excipient. .

In order to achieve the above object, the present invention is for nasal spray consisting of 10-20% by weight allergic rhinitis therapeutic drug, 60-80% by weight adhesive polymer, 1-10% by weight release control agent and 1-15% by weight bile salt. Provide microspheres.

The allergic rhinitis therapeutic drug used in the present invention is an active ingredient exhibiting a pharmacological effect by spraying the microspheres according to the present invention into the nasal cavity, and is used as a therapeutic agent for seasonal allergic rhinitis.

The allergic rhinitis treatment drug may be used as long as it is a drug used for the purpose of treating allergic rhinitis including antihistamine.

For example, antihistamines selected from the group consisting of fexofenadine, azelastine, cetirizine, levocetirizine, desloratadine and tecastemizole; Napazoline, oxymethazolin and xylometazoline; Anticholinergic agents selected from the group consisting of itratropium bromide, oxytropium bromide and tiotropium bromide; Steroids selected from the group consisting of budesonide, hydrocortisone and prednisolone; And an anti-allergic agent selected from the group consisting of chromoline sodium, montelukast and nedocromyl.

At this time, if a small amount of the allergic rhinitis treatment drug is used outside of the above range, the pharmacological effect as a desired purpose such as nasal congestion may not be obtained, while excessive use may cause side effects other than the pharmacological effect, and it is preferable in terms of economics. Not.

The adhesive polymer used in the present invention is a microsphere attached to the mucous membrane to perform the function of assisting the absorption while increasing the action time, consisting of hyaluronic acid, gelatin, collagen, chitosan, poly acrylic acid and cellulose derivatives Any one selected from the group is used, preferably hyaluronic acid is used.

In the microsphere of the present invention, if the adhesive polymer is used in a small amount out of the above range, the adhesiveness is not sufficiently obtained and is quickly lost in the mucosa, resulting in a problem of low bioavailability. It is not preferable because it may cause problems in use.

The release controlling agent used in the present invention is to control the release rate so that the active ingredient allergic rhinitis therapeutic drug from the microspheres according to the present invention for a certain time quickly, consisting of polyethylene glycol, mannitol and bovine serum albumin Any one selected from the group is used, and preferably, polyethylene glycol 1000, polyethylene glycol 6000, or polyethylene glycol 8000 is used.

The polyethylene glycol (PEG) is a liquid and solid polymer of the formula H (OCH ₂ CH ₂ ) _n OH having a weight average molecular weight in the range of about 200 to 20000, wherein n is 4 or more, PEG 1000, PEG 6000 and PEG 8000 has a weight average molecular weight of 950-1050, 5400-6600 and 7000-9000, respectively.

Using a small amount of the release controlling agent outside the above range in the microsphere of the present invention may make it difficult to release the drug from the microsphere so that the amount of absorption is reduced and thus may cause a problem in which sufficient drug efficacy cannot be expected. It is also undesirable because it is released too quickly and does not produce a lasting effect.

The bile salts used in the present invention are surfactants that perform a function of promoting nasal mucosal permeation of the microspheres according to the present invention, including taurodeoxycholic acid, ursodeoxycholic acid, taurocholic acid, glycocolic acid and taurodihydro Any salt selected from the group consisting of fusidic acid is used, preferably taurocholate.

In the microspheres of the present invention, the use of bile salts outside of the above ranges does not sufficiently improve drug absorption, whereas excessive use of the bile salts may cause problems by stimulating the nasal mucosa and causing toxicity.

The surface morphology and size of the microspheres according to the invention are observed by scanning electron microscopy (SEM), which have a smooth surface without special bending and have an average diameter in the range of 1 to 50 μm. To form a spherical shape.

The microspheres of the present invention may be formulated in a conventional pharmaceutical method by adding and mixing pharmaceutically acceptable conventional excipients or adjuvants, and preferably, by adding conventional excipients or auxiliaries, It may be formulated in a form.

At this time, the excipients used are, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like, and in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Can be.

When the microspheres of the present invention are used as nasal mucosal nebulizers, for example, an effective amount of fexofenadine hydrochloride is 10 to 150 mg / dose, preferably 30 to 60 mg / dose as fexofenadine.

In addition, the present invention comprises the steps of dissolving the adhesive polymer in distilled water; Dissolving an allergic rhinitis treatment drug including an antihistamine in alcohol; Mixing the adhesive polymer solution with the allergic rhinitis therapeutic drug solution; Adding a release controlling agent and a bile salt to the mixed reactants; And it provides a method for producing a nasal spraying microspheres comprising the step of spray drying the obtained reactant.

More specifically, the drug for treating allergic rhinitis at room temperature is dissolved in ethanol, the hyaluronic acid as an adhesive polymer is dissolved in water, then the two solutions are mixed, and then mixed again with polyethylene glycol 6000 and bile salt, and then the mixture is spray dried. To produce a microsphere according to the invention.

The spray drying conditions were carried out at a solution rate of 3-5ml / min, intake temperature 160 ℃ and exhaust temperature 90-110 ℃.

The microspheres according to the present invention can be easily administered to patients suffering from bitterness of the allergic rhinitis treatment drug including antihistamines and having difficulty in oral administration, and pharmacokinetic parameters, at least conventional oral preparations for treatment of allergic rhinitis Similar bioavailability can be obtained from that obtained in, so that it can be used as a nasal spray to show the desired efficacy.

Hereinafter, the present invention will be described in more detail with reference to fexofenadine hydrochloride, which is an antihistamine as an allergic rhinitis treatment drug. However, it is not limited by these examples.

<Examples 1 to 5> Preparation of microspheres

Hyaluronic acid (HA) was dissolved in secondary distilled water and fexofenadine hydrochloride (Fexo) was dissolved in ethanol, and the two solutions were mixed. Then, polyethylene glycol 6000 (PEG) and sodium taurocholic acid salt (NaTC) were added to the obtained mixture, respectively, and spray dryer machine (Buchi Mini-spray dryer, Buchi) at a rate of 3-5 ml / min at a temperature of 160 ° C. , Berman), and then sprayed to obtain dried microspheres. The spray drying conditions were intake temperature 160 ℃ and exhaust temperature 90-110 ℃, the content of each raw material was contained in the weight ratio shown in Table 1.

Example Composition (weight ratio) One HA: Fexo: PEG = 8: 2: 0 2 HA: Fexo: PEG = 8: 2: 1 3 HA: Fexo: PEG = 8: 2: 2 4 HA: Fexo: PEG: NaTC = 8: 2: 1: 1 5 HA: Fexo: PEG: NaTC = 8: 2: 1: 2

< Experimental Example  1 to 5> Microsphere  Property measurement

The physical properties of the microspheres prepared in the above examples were examined by dividing them into yield (%), drug content (% by weight), encapsulation degree (%), and average diameter (µm).

The yield of microspheres was calculated by the following equation.

Yield (%) = (W ₁ / W ₂ ) X 100

In this case, W ₁ is the weight of the dried microsphere, W ₂ means the sum of the initial dry weight of the raw material.

The content of the drug, fexofenadine, contained in the microspheres was determined by high performance liquid chromatography (HPLC).

Encapsulation (%) of the microspheres was calculated by Equation 2 below. High encapsulation efficiency means less loss of fexofenadine in the manufacture of microspheres.

Yield (%) = (W ₃ / W ₄ ) X 100

In this case, W ₃ is the actual content of fexofenadine in the prepared microsphere, W ₄ is theoretically the content of the fexofenadine in the microspheres.

The average diameter of the microspheres was measured using a scanning electron microscope (SEM), and SEM images of each microsphere were spherical about 20 μm, as shown in FIGS. 1A to 1E.

The results are shown in Table 2 below.

Example yield(%) Drug content (% by weight) Encapsulation Efficiency (%) Average diameter (㎛) One 24.06 19.4 97 26.9 2 24.9 17.52 96.3 16.0 3 26.67 16.2 97.2 22.5 4 16.05 15.5 92.8 21.4 5 16.05 14.9 96.8 32.5

< Experimental Example  6> Microsphere  Review of drug release effects

From each of the microspheres prepared in Example the amount of release of fexofenadine hydrochloride active ingredient in It was reviewed by in vitro dissolution test.

in In vitro dissolution test was carried out in a stirred water bath after each microsphere weighed to contain the same amount of fexofenadine 1.6mg into a semi-permeable membrane tube and 70ml of PBS (Phosphate buffered saline) of pH 6.4.

Samples were taken at defined times, filtered through a syringe filter, and analyzed using HPLC.

As a result, although the release rate was increased by the addition of polyethylene glycol 6000, as shown in Figure 2, even if the polyethylene glycol 6000 content is increased, the increase in release rate did not appear.

In addition, as shown in FIG. 3, the addition of sodium taurocholate did not appear to have a significant effect on the change in release rate.

< Experimental Example  7> Microsphere  Nasal mucosal permeation test

The epithelial cells isolated from human nasal mucosal tissue (human nasal mucosal epithelial cells supplied to Pusan Medical School's Otolaryngology) were cultured as monolayers in transwells using the ALI (Air-Lquid Interface) method, followed by TEER When the value reached 500Ω × cm ² or more, the permeation experiment was carried out.

In the experimental method, the microsphere prepared in Example was added to the apical side of the membrane, and the amount of fexofenadine permeated into the basolateral was analyzed by HPLC over time.

As a result, in the case of fexofenadine encapsulated in the microsphere as shown in Fig. 4, the fexofenadine solution (the same amount of pure fexofenadine powder contained in the microsphere is dissolved in a transport media containing 1% methanol in the microsphere). Compared with), absorption through the nasal mucosa was significantly improved.

< Experimental Example  8> Microsphere  Body dynamics test

The microspheres prepared in the above examples were administered to the rabbits by using a device manufactured by itself. Blood was collected from rabbit's ear artery and cut back by adding acetonitrile containing internal standard solution (propranool). After centrifugation, the supernatant was volatilized with nitrogen gas, the mobile phase was added, and quantified by molecular mass spectrometry (LC / MS / MS).

As a result, as shown in FIG. 5, the microspheres showed significantly higher blood concentrations when compared to fexofenadine solution and blood concentrations. In addition, as shown in Table 3, the microspheres of each example significantly increased AUC and Cmax and decreased Tmax. In this case, ND means a value not measured as below the detection limit.

Example AUC _inf (ngmin / ml) T _max (min) C _max (ng / ml) Solution (30% HPβCD) ND ND <5 2 29428.2 ± 14403.6 15 322.4 ± 38.1 4 39281.6 ± 10418.1 15 550.7 ± 216.5 5 42384.2 ± 14397.1 5 800.2 ± 372.1

Therefore, the microsphere formulation of the present invention is expected to greatly improve the bioavailability of the allergic rhinitis treatment drug including antihistamine.

1A to 1E show scanning electron micrographs of microspheres according to one embodiment;

Figure 2 shows the results of in vitro dissolution test for polyethylene glycol 6000 of the microspheres according to one embodiment,

Figure 3 shows the results of in vitro dissolution test for sodium taurocholic acid salt of microspheres according to one embodiment,

Figure 4 shows the results of the nasal mucosal permeation test of the microspheres using an nasal mucosal cell monolayer,

Figure 5 shows the results of the drug in vivo after absorption in the nasal mucosa in rabbits using fexofenadine solution as a microsphere and a control according to an embodiment.

Claims (8)

A nasal spray microsphere, comprising 10-20% by weight of an allergic rhinitis drug, 60-80% by weight of hyaluronic acid, 1-10% by weight of release controlling agent, and 1-15% by weight of bile salts. According to claim 1, wherein the allergic rhinitis treatment drug is antihistamine selected from the group consisting of fexofenadine, azelastine, cetirizine, levocetirizine, desloratadine and tecastemizole; Napazoline, oxymethazolin and xylometazoline; Anticholinergic agents selected from the group consisting of itratropium bromide, oxytropium bromide and tiotropium bromide; Steroids selected from the group consisting of budesonide, hydrocortisone and prednisolone; And chromoline sodium, montelukast, and nedocromyl. An intranasal spray microsphere, characterized in that any one selected from the group consisting of. delete The nasal spray microsphere according to claim 1, wherein the release controlling agent is any one selected from the group consisting of polyethylene glycol, mannitol and bovine serum albumin. The nasal cavity of claim 1, wherein the bile salt is a salt of any one bile acid selected from the group consisting of taurodeoxycholic acid, ursodeoxycholic acid, taurocholic acid, glycocolic acid, and taurodihydrofusidic acid. Spray microspheres. A nasal spray formulation containing the microspheres of any one of claims 1, 2, 4 and 5 and a pharmaceutically acceptable excipient. Dissolving hyaluronic acid in distilled water; Dissolving an allergic rhinitis therapeutic agent in alcohol; Mixing a hyaluronic acid solution with an allergic rhinitis therapeutic drug solution; Adding a release controlling agent and a bile salt to the mixed reactants; And Method for producing a nasal spraying microspheres comprising the step of spray drying the obtained reactant. 8. The method of claim 7 wherein the spray drying is carried out at a rate of 3-5 ml / min at a temperature of 160.

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