CN103816121A - Bepotastine besilate nasal spray and preparation method thereof - Google Patents

Abstract

The invention discloses a bepotastine besilate nasal spray and a preparation method thereof. For the nasal spray, 1-10 g of bepotastine besilate and 3-15 g of solubilizing composition are added in 100 mL of water; the solubilizing composition comprises components in percentage by weight as follows: 80%-95% of propylene glycol, polyethylene glycol 300 or polyethylene glycol 400 and the balance of caprylocaproyl macrogolglycerides; and pH of a nasal spray solution ranges from 6 to 8. In the composition, bepotastine besilate does not exist in a solid particle mode and cannot be crystallized during a long-term storage process, so that not only is rapid medicine absorption facilitated, but also a spray pump port is not blocked easily, and anaphylactic rhinitis and mucous membrane inflammation related to rhinitis can be cured effectively.

Description

Bepotastine besilate nasal mist and preparation method thereof

Technical field

The present invention relates to preparation of bepotastine besilate and preparation method thereof.

Background technology

Bepotastine besilate is the histamine H 1 receptor antagonist that a day Honda limit (Tanabe Seiyaku) company and Ube (UBE Industries) company develop jointly, within 2000, be used for the treatment of allergic rhinitis in Japan's approval, within 2002, approval is for urticaria/pruritus, sold in Japan by Mitsubishi Tanabe Pharma 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 the pruritus (eczematous dermatitis, prurigo, skin pruritus) that allergic rhinitis, urticaria, dermatosis cause.Its chemistry (+)-(S)-4-[4-[(4-chlorophenyl by name) (2-pyridine radicals) methoxyl group] piperidino] butanoic acid one benzene sulfonate, chemical structural formula is as follows:

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

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

For the treatment of allergic rhinitis, bepotastine nasal cavity topical obviously can be strengthened to therapeutic effect, suppress fast rhinitis symptom.Chinese patent 201180048106.3 has been announced a kind of bepotastine besilate compositions for symptoms such as nasal administration treatment rhinitis.In patent, adopt the sweeting agent taste maskings such as sucralose, add HPMC E15 LV or

suspending agent.Described in this patent, compositions pH is 4-9, containing bepotastine 0.5-8%w/v.Because the dissolubility of bepotastine besilate in water is slightly molten (1g solute is dissolved in 30～100ml solvent), in the compositions of this patent, bepotastine besilate may exist with solid particulate form, and easy crystallization in long-term storage process, both be unfavorable for the quick absorption of medicine, easily stopped up again spraying pumping hole.

Summary of the invention

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

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

Preferably, the bepotastine besilate that contains 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 composition buffering are 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 that can guarantee concentration 1～10g in 100ml water, obtain stable clarification nasal spray solution, and effectively avoid full-bodied propylene glycol or the impact of Polyethylene Glycol on atomizing particle size.The increase of spray particle diameter cause atomizing effect not good because full-bodied propylene glycol or Polyethylene Glycol can cause, therefore in spray, used in amounts will be controlled at certain scope, can guarantee good atomizing effect.

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

Preferably, take 100mL aqueous solvent as 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 to make the pH of nasal spray solution be 6～8 to the sodium hydroxide solution of 0.5～1.5mol/L;

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 regulate pH to 6～8 with sodium hydroxide solution, filter, can obtain described bepotastine besilate nasal mist.

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

The specific embodiment

Embodiment 1

Preparation method:

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

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

Above-mentioned nasal spray is carried out to three circulations of freezing-thawing test, circulate in lower 2 days of-10 ℃ of conditions at every turn, then under 40 ℃ of acceleration environments, investigate 2 days, sampling detects.The clarification of result solution, has no crystallization.

Embodiment 2

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

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

Above-mentioned nasal spray is carried out to three circulations of freezing-thawing test, circulate in lower 2 days of-20 ℃ of conditions at every turn, then under 40 ℃ of acceleration environments, investigate 2 days, sampling detects.The clarification of result solution, has no crystallization.

Embodiment 3

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

Above-mentioned nasal spray is placed with embodiment 1 low temperature, three circulations of freeze thawing, and solution clarification, has no crystallization.

Embodiment 4

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

Above-mentioned nasal spray is placed with embodiment 1 low temperature, three circulations of freeze thawing, and solution clarification, has no crystallization.

Embodiment 5

After the spray of embodiment 1～4 is sprayed with 100ul atomizing pump, LDSA-1400A determination of laser diffraction atomizing particle size, the atomizing particle size comparison with 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 granules

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

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

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

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

Claims (9)

1. bepotastine besilate nasal mist, is characterized in that, in 100mL water, and the bepotastine besilate that contains 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 (trade name labrasol) 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, the bepotastine besilate that contains 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, bepotastine besilate weight content 1～6g.

5. bepotastine besilate nasal mist according to claim 1, is characterized in that,

In 100mL water, also comprise the compatible antiseptic of pharmacy, osmotic pressure regulator, phosphate, pH adjusting agent and chelating agen.

6. bepotastine besilate nasal mist according to claim 5, is characterized in that, 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.

7. bepotastine besilate nasal mist, is characterized in that, take 100mL aqueous solvent as 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 to make the pH of nasal spray solution be 6～8 to the sodium hydroxide solution of 0.5～1.5mol/L;

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:

Propylene glycol, Liquid Macrogol or PEG400 80～95%

Labraso (trade name labrasol) surplus.

8. bepotastine besilate nasal mist according to claim 7, is characterized in that, 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.

9. the preparation method of the bepotastine besilate nasal cavity administrated preparation described in claim 5～8 any one, is characterized in that, comprises the steps:

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