CN103816121B - Bepotastine besilate nasal mist and preparation method thereof - Google Patents

Abstract

The invention discloses a kind of bepotastine besilate nasal mist and preparation method thereof, described nasal mist, in 100mL water, the bepotastine besilate containing 1 ~ 10g and the solubilizing composition of 3 ~ 15g; Described solubilizing composition is made up of the component of following percentage by weight: propylene glycol, Liquid Macrogol or PEG400 80 ~ 95%, Labraso surplus, and the pH of nasal spray solution is 6 ~ 8.In compositions of the present invention, bepotastine besilate does not exist in solid particulate form, and can not crystallization in long-term storage process, is not only beneficial to the quick absorption of medicine, and be not easy blocking spraying pumping hole, can effectively treatment of allergic rhinitis and the mucosal inflammation relevant with rhinitis.

Description

Bepotastine besilate nasal mist and preparation method thereof

Technical field

Preparation that the present invention relates to bepotastine besilate and preparation method thereof.

Background technology

Bepotastine besilate is the histamine H 1 receptor antagonist that day Honda limit (TanabeSeiyaku) company and Ube (UBEIndustries) company develop jointly, within 2000, be used for the treatment of allergic rhinitis in Japan's approval, approval in 2002 is used for urticaria/pruritus, sold in Japan by MitsubishiTanabePharma company, commodity are called Talion (smooth bright), are the agent of 10mg white film garment piece.Benzene sulphur bepotastine Pian Yi import China, is used for the treatment of allergic rhinitis, pruritus (eczematous dermatitis, prurigo, skin pruritus) that urticaria, dermatosis cause.Its chemistry (+)-(S)-4-[4-[(4-chlorophenyl) (2-pyridine radicals) methoxyl group] piperidino] butanoic acid one benzene sulfonate by name, chemical structural formula is as follows:

Bepotastine is a kind of non-sedating, high selectivity histamine (H1) acceptor inhibitor, to histamine H1-receptor, there is high selectivity inhibitory action, to 5-HT2, α 1, α 2 without affinity, Stabilization is had to mastocyte, when can suppress allergic inflammation, eosinophilic granulocyte is to the infiltration of inflammation part, and activation eosinophilic granulocyte's interleukin 5 (IL-5), leukotriene B4 (LTB4) and platelet activating factor (PAF) can be suppressed, alleviate allergic inflammation.The benzenesulfonic acid Beta department spit of fland eye drop of ISTAPharmaceuticals company goes on the market in the U.S. in August, 2009 through FDA approval, and trade name Bepreve, for the treatment of anaphylaxis conjunctivitis dependency eye pruritus.

Pharmacodynamics test shows: the dermoreaction that bepotastine can suppress histamine to cause; In vitro tests can suppress histamine to cause the contraction of guinea pig in vitro smooth muscle, suppress the passive intradermic anaphylactic reaction (PCA) of I property anaphylaxis model, the nasal cavity opposing of inhibition test allergic rhinitis model rise and the nasal mucosa vessels permeability of antigen induced hyperfunction, suppress the eosinophils that platelet activating factor and antigen cause, in the peripheral blood of suppression antigen induced, eosinophilic granulocyte's increases.

For the treatment of allergic rhinitis, bepotastine nasal cavity topical obviously can be strengthened therapeutic effect, suppress Rhinitis Symptoms fast.Chinese patent 201180048106.3 discloses a kind of bepotastine besilate compositions for symptoms such as nasal administration treatment rhinitis.Adopt the sweeting agent taste maskings such as sucralose in patent, add HPMC E15 LV or suspending agent.Compositions pH described in this patent is 4-9, containing bepotastine 0.5-8%w/v.Because the dissolubility of bepotastine besilate in water is slightly molten (1g solute dissolves is in 30 ~ 100ml solvent), in the compositions of this patent, bepotastine besilate may exist in solid particulate form, and easy crystallization in long-term storage process, both be unfavorable for the quick absorption of medicine, easily block spraying pumping hole again.

Summary of the invention

The object of this invention is to provide a kind of bepotastine besilate nasal mist and preparation method thereof, to overcome the above-mentioned defect that prior art exists.

Bepotastine besilate nasal mist of the present invention take water as carrier, in 100mL water, and the bepotastine besilate containing 1 ~ 10g and the solubilizing composition of 3 ~ 15g;

Preferably, the bepotastine besilate containing 2 ~ 8g and the solubilizing composition of 3 ~ 12g;

Described solubilizing composition is made up of the component of following percentage by weight:

Propylene glycol, Liquid Macrogol or PEG400 80 ~ 95%

Labraso (trade name labrasol) surplus

The pH of described nasal spray solution is 6 ~ 8;

Preferably, described bepotastine besilate nasal mist, also comprises the compatible antiseptic of pharmacy, osmotic pressure regulator, phosphate, pH adjusting agent and chelating agen;

Wherein:

Described antiseptic is potassium sorbate or benzalkonium chloride;

Described osmotic pressure regulator is anhydrous glucose or sodium chloride;

Described phosphate is dipotassium hydrogen phosphate or sodium hydrogen phosphate;

Described pH adjusting agent is sodium hydroxide;

Described phosphate and sodium hydroxide form cushion right;

Described chelating agen is disodiumedetate;

Applicant is on the basis of lot of experiments, unexpected discovery, what regulate described nasal spray solution is pH6 ~ 8, and add described solubilizing composition, the abundant dissolving of the bepotastine besilate of concentration 1 ~ 10g in 100ml water can be ensured, obtain stable clarification nasal spray solution, and effectively avoid full-bodied propylene glycol or Polyethylene Glycol on the impact of atomizing particle size.Because full-bodied propylene glycol or Polyethylene Glycol can cause the increase of spray particle diameter, cause atomizing effect not good, therefore in spray, used in amounts will control, in certain scope, can ensure good atomizing effect.

Preferably, in 100mL water, bepotastine besilate weight content is 1 ~ 8g, and particularly preferred is 1 ~ 6g;

Preferably, with 100mL aqueous solvent for benchmark, described bepotastine besilate nasal mist comprises the component of following percentage by weight:

Bepotastine besilate 2 ~ 8g

Disodiumedetate 0.01g ~ 0.05g

Phosphate 0.5-0.8g

Concentration is that the sodium hydroxide solution of 0.5 ~ 1.5mol/L makes the pH of nasal spray solution be 6 ~ 8;

Antiseptic 0.005 ~ 0.3g

Osmotic pressure regulator 0.2 ~ 1.6g;

Solubilizing composition 3 ~ 12g

The preparation method of bepotastine besilate nasal cavity administrated preparation of the present invention, comprises the steps:

Bepotastine besilate, disodiumedetate, antiseptic, osmotic pressure regulator, phosphate, solubilizing composition and water are mixed, then pH to 6 ~ 8 are regulated with sodium hydroxide solution, filter, described bepotastine besilate nasal mist can be obtained.

Nasal mist of the present invention uses with multiple dose form, and each sprayed volume is 20-100 μ L, can give different volumes dose as required.The adult every nostril of Chang Danci gives 100 μ l bepotastine besilate solution, administration every day 1 ~ 4 time, can effectively treatment of allergic rhinitis and the mucosal inflammation relevant with rhinitis.In compositions of the present invention, bepotastine besilate does not exist in solid particulate form, and can not crystallization in long-term storage process, is not only beneficial to the quick absorption of medicine, and is not easy blocking spraying pumping hole.

Detailed description of the invention

Embodiment 1

Preparation method:

Bepotastine besilate, disodiumedetate, sodium hydrogen phosphate, anhydrous glucose, propylene glycol, Labraso, benzalkonium chloride 80ml pure water are dissolved, mixing, add 1mol/L sodium hydroxide and regulate pH to 6.5, add 20ml pure water, mixing, filters, fill, add atomizing pump, obtain solution-type nasal mist.

Above-mentioned nasal spray is carried out low-temperature test three circulations, circulate in lower 2 days of 2 DEG C of conditions at every turn, then under 40 DEG C of acceleration environments, investigate 2 days, sampling detects, and result solution is clarified, and has no crystallization.

Above-mentioned nasal spray is carried out freezing-thawing test three circulations, circulate in lower 2 days of-10 DEG C of conditions at every turn, then under 40 DEG C of acceleration environments, investigate 2 days, sampling detects.Result solution is clarified, and has no crystallization.

Embodiment 2

Preparation method is with embodiment 1.Obtain solution-type nasal mist.

Above-mentioned nasal spray is carried out low-temperature test three circulations, circulate in lower 2 days of 8 DEG C of conditions at every turn, then under 40 DEG C of acceleration environments, investigate 2 days, sampling detects, and result solution is clarified, and has no crystallization.

Above-mentioned nasal spray is carried out freezing-thawing test three circulations, circulate in lower 2 days of-20 DEG C of conditions at every turn, then under 40 DEG C of acceleration environments, investigate 2 days, sampling detects.Result solution is clarified, and has no crystallization.

Embodiment 3

Preparation technology is with embodiment 1.Obtain solution-type nasal mist.

Placed with embodiment 1 low temperature, freeze thawing three circulation by above-mentioned nasal spray, solution is clarified, and has no crystallization.

Embodiment 4

Preparation technology is with embodiment 1.Obtain solution-type nasal mist.

Placed with embodiment 1 low temperature, freeze thawing three circulation by above-mentioned nasal spray, solution is clarified, and has no crystallization.

Embodiment 5

By the spray of embodiment 1 ~ 4 with after the spraying of 100ul atomizing pump, LDSA-1400A determination of laser diffraction atomizing particle size, compares with the atomizing particle size of pure water, has no atomizing particle size significant change.The results are shown in Table 1.

	D10((μm)	D50(μm)	D90(μm)	SMD(μm)
					Pure water	43.61	71.81	102.36	57.92
Embodiment 1	46.28	70.98	103.32	66.25
					Embodiment 2	42.94	67.44	103.62	62.71
Embodiment 3	43.36	66.56	97.78	61.95
					Embodiment 4	42.23	77.67	116.93	56.41

D10 (10% particle diameter): example: the granule below XXX micron is 10% of the volume of whole granule

D50 (50% particle diameter): example: the granule below XXX micron is 50% of the volume of whole granule

D90 (90% particle diameter): example: the granule below XXX micron is 90% of the volume of whole granule

SMD: bulk area mean diameter, Σ d*d*dn/ Σ d*dn

Table 1 data show, add solubilizing composition in embodiment 1 ~ 4, and do not cause the spray particle diameter of bepotastine besilate to increase, atomizing effect is better.

Claims (7)

1. bepotastine besilate nasal mist, is characterized in that, in 100mL water, and the bepotastine besilate containing 1 ~ 10g and the solubilizing composition of 3 ~ 15g;

Described solubilizing composition is made up of the component of following percentage by weight:

Liquid Macrogol or PEG400 80 ~ 95%

Labraso surplus

The pH of described nasal spray solution is 6 ~ 8.

2. bepotastine besilate nasal mist according to claim 1, is characterized in that, in 100mL water, and the bepotastine besilate containing 2 ~ 8g and the solubilizing composition of 3 ~ 12g.

3. bepotastine besilate nasal mist according to claim 1, is characterized in that, in 100mL water, bepotastine besilate weight content is 1 ~ 8g.

4. bepotastine besilate nasal mist according to claim 1, is characterized in that, in 100mL water, and bepotastine besilate weight content 1 ~ 6g.

5. bepotastine besilate nasal mist according to claim 1, it is characterized in that, in 100mL water, also comprise the compatible antiseptic of pharmacy, osmotic pressure regulator, phosphate, pH adjusting agent and chelating agen, described antiseptic is potassium sorbate or benzalkonium chloride; Described osmotic pressure regulator is anhydrous glucose or sodium chloride; Described phosphate is dipotassium hydrogen phosphate or sodium hydrogen phosphate; Described pH adjusting agent is sodium hydroxide; Described chelating agen is disodiumedetate.

6. bepotastine besilate nasal mist, is characterized in that, with 100mL aqueous solvent for benchmark, comprises the component of following percentage by weight:

Bepotastine besilate 2 ~ 8g

Disodiumedetate 0.01g ~ 0.05g

Phosphate 0.5-0.8g

Concentration is that the sodium hydroxide solution of 0.5 ~ 1.5mol/L makes the pH of nasal spray solution be 6 ~ 8;

Antiseptic 0.005 ~ 0.3g

Osmotic pressure regulator 0.2 ~ 1.6g

Solubilizing composition 3 ~ 12g

Described solubilizing composition is made up of the component of following percentage by weight:

Liquid Macrogol or PEG400 80 ~ 95%

Labraso surplus,

Described antiseptic is potassium sorbate or benzalkonium chloride; Described osmotic pressure regulator is anhydrous glucose or sodium chloride; Described phosphate is dipotassium hydrogen phosphate or sodium hydrogen phosphate.

7. the preparation method of the bepotastine besilate nasal cavity administrated preparation described in any one of claim 5 ~ 6, is characterized in that, comprise the steps:

Bepotastine besilate, disodiumedetate, antiseptic, osmotic pressure regulator, phosphate, solubilizing composition and water are mixed, then pH to 6 ~ 8 are regulated with sodium hydroxide solution, filter, described bepotastine besilate nasal mist can be obtained.