CN104027306A - Paroxetine oral suspension and preparation method thereof - Google Patents

Abstract

The invention discloses oral suspension containing medicine resin salt of Paroxetine and salts of Paroxetine. The oral suspension is an antidepressant, is stable in property and is good in taste.

Description

Paroxetine oral administration mixed suspension and preparation method thereof

Technical field

The invention belongs to field of pharmaceutical preparations, more relate to a kind of oral mixed suspension solution of the medical resin salt that comprises paroxetine (Paroxetine) and salt thereof, its stable in properties and there is good mouthfeel.

Background technology

Paroxetine (Paroxetine), its chemical name is: (-)-trans-4R-(4-fluorophenyl)-3S-{[3 ', 4 '-(methylene-dioxy) phenoxy group] methyl }-piperidines(1:1) salt acid-addition salts.Be usually used in clinically depression and compulsive treatment.

Paroxetine is the antidepressants of a kind of selective serotonin reuptake inhibithors (SSRI) type, its drug form is paroxetine hydrochloride (Paroxetine hydrochloride), commodity " seroxat " by name ordinary tablet (Seroxat), it is a kind of high selectivity serotonin reuptake inhibitor, by what stop 5-hydroxy tryptamine, absorb again the concentration that improves 5-hydroxy tryptamine in nerve synapse gap, enhancing maincenter 5-hydroxy tryptamine function of nervous system, thus antidepressant effect produced.

This compound is used for human body by approval, and as the many countries sale in the whole world of a kind of antidepressant preparation.Paroxetine listing dosage form is mainly oral tablet at present, yet some patient for example: child and old man are taking the problem that often runs into dysphagia, therefore need to develop the row of being obedient to that oral liquid improves patient.But because paroxetine has very strong bitterness, during with drink form, this bitterness is obvious especially, secondly, stability of Oral is poor, and effect duration is short.So be prepared into suspension, can not only effectively cover bitterness, can also increase greatly the stability of preparation, improve effect duration.

Summary of the invention

The present invention discloses a kind of stable in properties, the good oral administration mixed suspension of mouthfeel, and described suspension comprises effective ingredient (-)-trans-4R-(4-fluorophenyl)-3S-{[3 ', 4 '-(methylene-dioxy) phenoxy group] methyl }-piperidinesand the medical resin salt of salt and Amberlite series plastics, described suspension is included in this suspension and adds suspending agent, antiseptic, and correctives, and its acid-base value is adjusted between pH3-8.

The present invention coordinates Amberlite series plastics formation medical resin with paroxetine, and adds aerosil to be prepared into suspension, and adds antiseptic, can effectively improve the stability of preparation.At propylene glycol: prepare medical resin salt in water (1:1) medium standby, high temperature 70-80 ℃ aqueous medium adds preservative and sweetener, adds suspending agent under stirring condition, and the cooling medical resin salt that adds, obtains oral administration mixed suspension to be prepared next time.

Wherein (-)-trans-4R-(4-fluorophenyl)-3S-{[3 ', 4 '-(methylene-dioxy) phenoxy group] methyl } the medicine and pharmacology acceptable addition salt of-piperidines is 1:1 salt acid-addition salts.

Wherein the mol ratio of Amberlite and paroxetine is 1:2-2:1.

Wherein Amberlite series plastics is weak-acid cation-exchange resin, is selected from Amberlite IRP-88, wherein one or more of Amberlite IRP-64 and Amberlite IRP-69.Amberlite series weak-acid cation-exchange resin can coordinate with medicine formation medical resin, effectively covers the bitterness of medicine.

The antiseptic that described paroxetine oral administration mixed suspension comprises is benzoic acid, and its concentration, between 0.1mg/mL to 2 mg/mL, is damaged oral administration mixed suspension in order to prophylaxis of microbial.

Wherein pharmaceutically acceptable sweetener packets contains the preferably sweeting agent of at least one reinforcement, for example: glucide, saccharin sodium and calcium, aspartame, Ai Si divide potassium, cyclamate, acesulfame potassium, LaspartylLphenylalanine methylester, encircle dithiocarbamic acid sodium, Ali is sweet, dihydro is looked into ketone, Mo Lin, Flos Chrysanthemi essence, 1,4,6-sucralose, acesulfame potassium, preferably is saccharin sodium.The bulk sweetener needing, such as: Sorbitol, mannitol, fructose, sucrose, maltose, lactose, glucose, xylitol etc.

The sweeting agent of strengthening is generally used under low concentration, and for example the concentration of saccharin sodium is between 0.01% to 0.1%w/v, and preferably approximately 0.05%.Bulk sweetener, for example Sorbitol can be effectively for relatively large scope, and approximately 30% to 50%w/v, and preferably approximately 40%.

Essence pharmaceutically acceptable, that can cover bitter principle, preferably is fruit-like flavour, for example: Fructus Pruni pseudocerasi, honey peach, Fructus Fragariae Ananssae, orange taste, Herba Menthae local flavor, hami melon etc. are at pharmaceutically acceptable strong taste essence.Preferably essence concentration between 0.05% to 1%w/v.The combination of this strong taste spice of use that can be favourable, preferably makes its sense of taste and color under the acid condition of formula not have any change or forfeiture, and does not affect the character of other compositions in formula while using spice.

specific embodiment:

1mol paroxetine hydrochloride is joined to a certain amount of propylene glycol with the AmberliteIRP-64 of 0.5,1,2mol respectively: in water (1:1) solution, as for allowing toner be dispersed in solution in water bath with thermostatic control agitator, shaken overnight under room temperature.Adopt vacuum filter by resin salt and fluid separation applications, afterwards by a small amount of water cleaning resin salt three times, the resin after sucking filtration is placed on the medical resin salt that dried overnight in 60 degrees Celsius of vacuum drying ovens obtains paroxetine.

The oral liquid of the paroxetine-AmberliteIRP-64 medical resin salt that contains different mol ratio according to table 1 preparation, selects 10 volunteers to evaluate bitterness by blind method research oral administration mixed suspension at random, is recorded as 1 to 5 minute.The taste masking effect of assessment AmberliteIRP-64 to paroxetine.

The impact of table 1 AmberliteIRP-64 consumption on mouthfeel

Compound	Prescription 1	Prescription 2	Prescription 3
				Medical resin salt	2:1	1:1	1:2
Microcrystalline Cellulose CL611	30 mg/mL	30 mg/mL	30 mg/mL
				Orange taste essence	1mg/mL	1mg/mL	1mg/mL
Sorbitol 70%(w/v)	400mg/mL	400mg/mL	400mg/mL
				Methyl parahydroxybenzoate	0.5mg/mL	0.5mg/mL	0.5mg/mL
Propyl p-hydroxybenzoate	0.5mg/mL	0.5mg/mL	0.5mg/mL

The affect result of table 2 AmberliteIRP-64 consumption on mouthfeel

Experimenter	Prescription 1	Prescription 2	Prescription 3
				A	1	3	4
B	3	2	3
				C	2	4	4
D	3	3	3
				E	3	3	3
F	1	2	3
				G	2	3	2
H	2	2	4
				I	3	4	3
J	4	4	3
				Average score	2.4	3	3.2

Note: 5-mouthfeel is very good, and 4-mouthfeel is better, and 3-mouthfeel is general, and 1-mouthfeel is bad

When the mol ratio of paroxetine and AmberliteIRP-64 is 1:1, can play the effect of significantly covering bitterness.When the consumption of AmberliteIRP-64 continues to increase the effect that has not improved significantly.So select paroxetine: the medical resin salt that the ratio of AmberliteIRP-64 is 1:1.In order further to improve mouthfeel, intend regulating kind and the consumption of correctives in prescription.

Embodiment 2: comparative study

2 kinds of essence (orange taste essence and strawberry essence) and two kinds of sweeting agents (Sorbitol 70%(w/v) and saccharin sodium merge are used in assessment) after the taste of feeling and pleasant impression.10 volunteers of random selection evaluate its sugariness, fruity, the sensations such as bitterness by blind method research to including the oral mixed suspension formula of liquid (as shown in table 2) of one of two kinds of spice.

The impact on mouthfeel of table 3 sweeting agent and essence

Compound	Prescription 1	Prescription 2	Prescription 3	Prescription 4
					Orange taste essence (mg/mL)	0.5	1.5	?	?
Strawberry essence (mg/mL)	-	-	0.5	1.5
					Sorbitol 70%(w/v) (mg/mL)	300	500	300	500
Saccharin sodium (mg/mL)	0.5	0.5	1.0	1.0
					Methyl parahydroxybenzoate (mg/mL)	0.5	0.5	0.5	0.5
Propyl p-hydroxybenzoate (mg/mL)	0.5	0.5	0.5	0.5

With this two formula, delivering 10 volunteers tests.Compliance response variables (sugariness, fruity, the mark of bitterness sensation) is recorded as 1 to 5 minute.Whether the unidirectional ANOVA method of usage data analytical data has significant difference.

Table 4 sweeting agent and the essence result on mouthfeel impact

Experimenter	Prescription 4	Prescription 2	Prescription 3	Prescription 4
					A	3	4	2	3
B	3	5	3	5
					C	5	3	4	4
D	3	2	3	3
					E	3	5	3	3
F	4	3	5	4
					G	3	5	3	2
H	4	4	2	3
					I	3	4	3	3
J	4	3	4	4
					Average score	3.5	3.8	3.2	3.4

Note: 5-mouthfeel is very good, and 4-mouthfeel is better, and 3-mouthfeel is general, the bad (*: P<.0.05) of 1-mouthfeel

In general, saccharin sodium is at concentration 0.5mg/mL, and Sorbitol (70%w/v) has preferably score when concentration is 500mg/mL.Orange taste essence is better than strawberry essence, and the sugariness of orange taste essence is little compared with strawberry essence, and has fruit-like flavour.But all formulas all have slight anesthesia sensation on tongue.P-Hydroxybenzoate odorless or have slight special aroma, mildly bitter flavor, the fiber crops of burning, so the anesthesia sense on this tongue may be from the p-Hydroxybenzoate using as antiseptic, so we adopt benzoic acid further to compare research.

Embodiment 3: comparative study

The random oral mixed suspension formula of liquid of selecting 10 volunteers to adopt one of two kinds of antiseptic of blind method research (p-Hydroxybenzoate or benzoic acid), evaluates its its sugariness, fruity, bitterness and the sensations such as anesthesia sense on tongue

The impact of table 5 antiseptic on mouthfeel

Compound	Prescription 1	Prescription 2
			Orange taste essence (mg/mL)	1	1
Sorbitol 70%(w/v) (mg/mL)	500	500
			Saccharin sodium (mg/mL)	0.5	0.5
Methyl parahydroxybenzoate (mg/mL)	0.5	-
			Propyl p-hydroxybenzoate (mg/mL)	0.5	-
Benzoic acid (mg/mL)	-	1.0

According to this two formulated oral liquid, deliver 10 volunteers and test.Compliance response variables (sugariness, fruity, the mark of bitterness and anesthesia sensation) is recorded as 1 to 5 minute.Whether the unidirectional ANOVA method of usage data analytical data has significant difference.

The result of table 6 antiseptic on mouthfeel impact

Experimenter	Prescription 1	Prescription 1
			A	3	5
B	4	4
			C	5	3
D	4	5
			E	3	4
F	3	4
			G	5	5
H	4	4
			I	5	4
J	4	5
			Average score	4.0	4.3

Note: 5-mouthfeel is very good, and 4-mouthfeel is better, and 3-mouthfeel is general, the bad (*: P<.0.05) of 1-mouthfeel

Generally speaking, under benzoic acid exists, do not feel the sensation of anesthesia, in the oral liquid that includes methyl parahydroxybenzoate and propyl p-hydroxybenzoate, can feel slight anesthesia sense.Table 4 is listed the compositions of the most extensively being recommended by volunteer.

The better oral liquid prescription of table 7

Compound	Concentration (mg/mL)
		Paroxetine hydrochloride: Amberlite IRP-64	1:1
Microcrystalline Cellulose CL611	30
		Orange taste essence	1.0
Sorbitol 70%(w/v)	500
		Saccharin sodium	0.5
Aerosil	30
		Benzoic acid	1.0

Add sodium hydroxide and regulate pH to 5.0.

Claims (10)

1. the oral mixed suspension solution of a medical resin salt that contains paroxetine (Paroxetine) and salt thereof, its soda acid pH value is between 3-8, wherein comprise (-)-trans-4R-(4-fluorophenyl)-3S-{[3 ', 4 '-(methylene-dioxy) phenoxy group] methyl } the medical resin salt of-piperidines and salt and Amberlite series plastics.

2. the oral mixed suspension solution of a kind of medical resin salt that contains paroxetine (Paroxetine) and salt thereof as claimed in claim 1, wherein further comprises benzoic acid.

3. as claimed in claim 1, wherein Amberlite series plastics is weak-acid cation-exchange resin, is selected from Amberlite IRP-88, wherein one or more of Amberlite IRP-64 and Amberlite IRP-69.

4. oral administration mixed suspension as claimed any one in claims 1 to 3, wherein the mol ratio of Amberlite and paroxetine is 1:2-2:1.

5. oral administration mixed suspension as claimed any one in claims 1 to 3, wherein (-)-trans -4R-(4-fluorophenyl)-3S-{[3 ', 4 '-(methylene-dioxy) phenoxy group] methyl }-piperidinesmedicine and pharmacology acceptable addition salt be 1:1 salt acid-addition salts.

6. the oral administration mixed suspension as described in claim 1,2, wherein benzoic consumption is between 0.1 mg/mL to 2mg/mL.

7. oral administration mixed suspension as claimed any one in claims 1 to 3, wherein soda acid pH value is between 3-8.

8. oral administration mixed suspension as claimed any one in claims 1 to 3, further contains bulk sweetener, its concentration between 30% to 50%w/v; The sweeting agent of strengthening, its concentration between 0.01% to 0.1%w/v; And essence, concentration between 0.05% to 1%w/v.

9. the oral administration mixed suspension as described in claim 1-8, wherein bulk sweetener is wherein one or more of Sorbitol, mannitol, fructose, sucrose, maltose, lactose, glucose, xylitol; The sweeting agent of strengthening is that glucide, saccharin sodium and calcium, aspartame, Ai Si divide potassium, cyclamate, acesulfame potassium, LaspartylLphenylalanine methylester, encircle dithiocarbamic acid sodium, Ali is sweet, dihydro is looked into ketone, Mo Lin, Flos Chrysanthemi essence, 1,4,6-sucralose, wherein one or more of acesulfame potassium, preferably is saccharin sodium; Essence, preferably is fruit-like flavour, as Fructus Pruni pseudocerasi, honey peach, Fructus Fragariae Ananssae, orange taste, Herba Menthae local flavor, wherein one or more such as hami melon.

10. a stable in properties, the good oral administration mixed suspension of mouthfeel, described suspension comprises effective ingredient (-)-trans-4R-(4-fluorophenyl)-3S-{[3 ', 4 '-(methylene-dioxy) phenoxy group] methyl }-piperidinesand the medical resin salt of salt and Amberlite series plastics, described suspension is included in this suspension and adds suspending agent, antiseptic, and correctives, and its acid-base value is adjusted between pH3-8.