CN101028267A - Stabilized Parinaudsijones large-capacity injection - Google Patents

Abstract

A stable high-capacity injection of Paluonuosiqiong or its medicinal salt for treating the vomiting reaction caused by chemcotherapy or radiotherapy of cancer with low irritation and high compliance is disclosed.

Description

A kind of stable Parinaudsijones large-capacity injection

Technical field

The present invention relates to the injection of palonosetron or its officinal salt, especially a kind of stable high-capacity injection, the vomiting reaction when can be used for cancer chemotherapy, radiotherapy.

Background technology

Palonosetron is 5-hydroxy tryptamine 3 receptor antagonists that Switzerland Helsinn Healthcare company develops, in JIUYUE, 2003 is at the U.S.'s its injection (small-volume injection that goes on the market, specification: 0.25mg/5ml), the vomiting reaction when being mainly used in cancer chemotherapy, radiotherapy clinically.

U.S. Pat 5202333 discloses an oral liquid prescription of palonosetron Hcl in embodiment 13, an injection prescription and a tablet formulation.In disclosed injection prescription, palonosetron Hcl concentration is 10-100mg/ml, has adopted adjuvants such as dextran, citric acid monohydrate compound and sodium hydroxide.

WO2004067005 discloses a kind of chemotherapy antiemetic palonosetron Hcl liquid preparation that is used for, wherein the palonosetron Hcl concentration range is 0.01mg/ml to 5.0mg/ml, preferred 0.05mg/ml, the pH value scope is 4.0-6.0, and adjuvant is citric acid, trisodium citrate, EDTA, mannitol etc.

A kind of stable injection of palonosetron is disclosed among the CN1682728, wherein the palonosetron Hcl concentration range is 0.01mg/ml to 9.0mg/ml, preferred 0.25mg/ml, the pH value scope is 3.0-4.0, adjuvant is glucose, citric acid, trisodium citrate etc.

Because existing injection of palonosetron concentration height, zest is bigger during use, poor compliance when clinical application.Therefore, we are prepared into high-capacity injection with palonosetron, than the little liquid drugs injection of palonosetron Hcl, have reduced its zest, have improved the compliance of medication, and clinical easy to use, are difficult for causing secondary pollution and and patient infection and generation pyrogen reaction.

Summary of the invention

Palonosetron of the present invention refers to 3aS)-2-[(S)-and 1-nitrogen bicyclo-[2.2.2] oct-3-yl]-2,3,3a, 4,5,6-six hydrogen-1-oxygen-1H benzene [de] isoquinolin hydrochloride preferably exist with single hydrochloride.The structure of palonosetron Hcl list hydrochloride is as follows:

" pharmaceutically acceptable " refer to use in pharmaceutical compositions, normally safe, nontoxic and neither neither other aspects not expecting biologically and comprise for veterinary purpose and people's pharmaceutical applications acceptable.

" pharmaceutically acceptable salt " refers to that it is a pharmaceutically acceptable salt, as above-mentioned definition, has required pharmacological activity.Such salt comprises the acid-addition salts that mineral acid forms, and described mineral acid is hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. for example; Or the acid-addition salts of organic acid formation, described organic acid is acetic acid, propanoic acid, caproic acid, enanthic acid, Pentamethylene. propanoic acid, hydroxyacetic acid, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, glutamic acid, salicylic acid methanesulfonic acid etc. for example.

In addition, when the acid proton that exists can react with inorganic or organic base, formed its pharmaceutically acceptable salt.Acceptable inorganic base comprises sodium hydroxide, sodium carbonate, potassium hydroxide, aluminium hydroxide and calcium hydroxide.Acceptable organic base comprises ethanolamine, diethanolamine, triethanolamine etc.

The invention provides a kind of stable injection of palonosetron, comprise 0.00001 to 0.0099mg/ml palonosetron or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, preferred 0.0001 to 0.0099mg/ml, most preferably 0.0025mg/ml.

Injection pH value scope of the present invention is 3.0-8.0, preferred 6.0-8.0, most preferably 6.5-7.5.

PH value regulator of the present invention comprises mineral acid, and described mineral acid is hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. for example; Or the acid-addition salts of organic acid formation, described organic acid is acetic acid, propanoic acid, caproic acid, enanthic acid, Pentamethylene. propanoic acid, hydroxyacetic acid, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, glutamic acid, salicylic acid methanesulfonic acid etc. for example; Acceptable inorganic base comprises sodium hydroxide, sodium carbonate, potassium hydroxide, aluminium hydroxide and calcium hydroxide.Acceptable organic base comprises ethanolamine, diethanolamine, triethanolamine etc.Wherein preferred hydrochloric acid and sodium hydroxide.

The osmotic pressure regulator of injection of the present invention is glucose, sodium chloride and mannitol etc., preferred sodium chloride.

The present invention also can use antioxidant, for example antioxidant commonly used such as sodium pyrosulfite, sodium sulfite, sodium sulfite, sodium thiosulfate and ascorbic acid, preferably sodium sulfite or ascorbic acid.

The present invention also can charge into the anti-oxidation of noble gas in container, as nitrogen or carbon dioxide, preferred nitrogen.Further set forth the present invention by the following examples, but be not limited to embodiment.

The specific embodiment

Embodiment 1

Prescription is formed specification (30ml:0.25mg)

Palonosetron Hcl 0.25mg

Sodium chloride 240mg

Sodium sulfite 1mg

PH value 6.0-8.0

Water for injection 30ml

According to the prescription proportioning, take by weighing the palonosetron Hcl of recipe quantity and required pharmaceutic adjuvant respectively, add the entry stirring and dissolving, regulate pH to 6.0-8.0, applied activated carbon depyrogenation, packing with hydrochloric acid and sodium hydroxide, in bottle, charge into nitrogen, capping plug gland, 100 ℃ of steam sterilizations 30 minutes.

Embodiment 2

Prescription is formed specification (50ml:0.25mg)

Palonosetron Hcl 0.25mg

Sodium chloride 400mg

Ascorbic acid 1.5mg

PH value 6.5-7.5

Water for injection 50ml

According to the prescription proportioning, take by weighing the palonosetron Hcl of recipe quantity and required pharmaceutic adjuvant respectively, add the entry stirring and dissolving, regulate pH to 6.5-7.5, applied activated carbon depyrogenation, packing with hydrochloric acid and sodium hydroxide, in bottle, charge into nitrogen, capping plug gland, 100 ℃ of steam sterilizations 30 minutes.

Embodiment 3

Prescription is formed specification (100ml:0.25mg)

Palonosetron Hcl 0.25mg

Sodium chloride 850mg

Sodium sulfite 3mg

PH value 6.5-7.5

Water for injection 100ml

According to the prescription proportioning, take by weighing the palonosetron Hcl of recipe quantity and required pharmaceutic adjuvant respectively, add the entry stirring and dissolving, regulate pH to 6.5-7.5, applied activated carbon depyrogenation, packing with hydrochloric acid and sodium hydroxide, in bottle, charge into nitrogen, capping plug gland, 100 ℃ of steam sterilizations 30 minutes.

Embodiment 4

Prescription is formed specification (250ml:0.25mg)

Palonosetron Hcl 0.25mg

Glucose 12g

Ascorbic acid 1.5mg

PH value 6.0-7.0

Water for injection 250ml

According to the prescription proportioning, take by weighing the palonosetron Hcl of recipe quantity and required pharmaceutic adjuvant respectively, add the entry stirring and dissolving, regulate pH to 6.0-7.0, applied activated carbon depyrogenation, packing with hydrochloric acid and sodium hydroxide, in bottle, charge into nitrogen, capping plug gland, 100 ℃ of steam sterilizations 30 minutes.

Embodiment 5

Prescription is formed specification (500ml:0.25mg)

Palonosetron Hcl 0.25mg

Sodium chloride 4g

Ascorbic acid 4mg

PH value 6.5-7.5

Water for injection 500ml

According to the prescription proportioning, take by weighing the palonosetron Hcl of recipe quantity and required pharmaceutic adjuvant respectively, add the entry stirring and dissolving, regulate pH to 6.5-7.5 with hydrochloric acid and sodium hydroxide, applied activated carbon depyrogenation, 100 ℃ of steam sterilizations 30 minutes.

Embodiment 6

Adopt 40 ℃ of prepared injection liquid samples of the present invention to carry out stability test in 3 months, the result shows that the prepared sample stability of the present invention is good.

40 ℃ of 3 months study on the stability results of table 1 palonosetron Hcl injection

	Outward appearance		PH value		HPLC impurity peak area (%)
								0 day	3 the end of month	0 day	3 the end of month	0 day	3 the end of month
Embodiment 1 sample	Colourless clear liquid	Colourless clear liquid	6.32	6.41	0.15	0.28
							Embodiment 2 samples	Colourless clear liquid	Colourless clear liquid	6.93	7.01	0.14	0.31
Embodiment 3 samples	Colourless clear liquid	Colourless clear liquid	7.03	6.99	0.18	0.32
							Embodiment 4 samples	Colourless clear liquid	Colourless clear liquid	6.35	6.41	0.16	0.28
Embodiment 5 samples	Colourless clear liquid	Colourless clear liquid	7.21	7.18	0.11	0.24

Embodiment 7 animal irritation tests

Adopt the prepared injection liquid samples of the present invention to carry out the animal irritation test under the same conditions with external commercially available sample.The injection liquid samples zest of the present invention's preparation is starkly lower than external commercially available sample as can be known from the results.

Method: get 16 of healthy rabbits, male and female half and half, be divided into 4 groups at random, 4 every group, first group of auricular vein injection embodiment 2 samples (self-control sample) 1ml/ only, second group of capacity embodiment 3 sample (self-control sample) such as auricular vein injection, the 3rd group of external commercially available sample of capacity such as auricular vein injection, the 4th group of capacity normal saline solution such as auricular vein injection, 2 minutes inject time, once a day, continuous 5 days.Last was injected back 48 hours, and the blood vessel of first perusal injection site and the variation of surrounding tissue are got 2 rabbit for every group then, are the center with the injection site, and it is fixing in 10% formalin to cut the rabbit ear (containing blood vessel) 3-5cm, carries out histopathologic examination.In addition 2 rabbit are behind the last drug administration by injection the 7th day, the variation of perusal injection site, and operation as stated above, and according to perusal and histopathologic examination's judged result.

The result:

Perusal as a result experimental result show that 48h self-control sample is not seen reactions such as tangible hyperemia, edema after the intravenous injection of rabbit ear last, and external commercially available sample has certain edema reaction; Observe the self-control sample behind the 7d and do not see reactions such as tangible hyperemia, edema, and external commercially available sample there is certain edema reaction.See Table 2.

2. 48h after histopathologic examination's ear vein last administration as a result makes sample by oneself with physiology saline control group basically identical, and external commercially available sample degree of taking a favourable turn and intermediate edema, hyperemia and a small amount of inflammatory cell infiltration; Edema does not have obviously and alleviates after 7 days, but every index does not have obvious pathological change.Show that administration has certain zest to external commercially available sample to ear vein.See Table 3.

Perusal result after the administration of table 2 last

Group	Observing time	No significant reaction	Congested	Edema	Degeneration	Scleroma	Downright bad
								The external commercially available sample of external commercially available sample normal saline solution embodiment 2 sample embodiment 3 samples of normal saline solution embodiment 2 sample embodiment 3 samples	48h 48h 48h 48h 7d 7d 7d 7d	4/4 4/4 4/4 3/4 2/2 2/2 2/2 1/2	0/4 0/4 0/4 0/4 0/2 0/2 0/2 0/2	0/4 0/4 0/4 1/4 0/2 0/2 0/2 1/2	0/4 0/4 0/4 0/4 0/2 0/2 0/2 0/2	0/4 0/4 0/4 0/4 0/2 0/2 0/2 0/2	0/4 0/4 0/4 0/4 0/2 0/2 0/2 0/2

48h and 7 days lesion degrees after the administration of table 3 last

Group	Observing time	Venectasia hyperemia	Thrombosis	Edema	Hemorrhage	Inflammatory cell infiltration	Scleroma	Downright bad
									Normal saline solution embodiment 2 samples	48h 48h	0～+ 0～+	- -	0～+ 0～+	- -	0～+ 0～+	- -	- -

The external commercially available sample of external commercially available sample normal saline solution embodiment 2 sample embodiment 3 samples of embodiment 3 samples

48h 48h 7d 7d 7d 7d

0～+ 0～+ 0～+ 0～+ 0～+ 0～+

- - - - - -

0～+ 0～+++ 0～+ 0～+ 0～+ 0～+++

- - - - - -

0～+ 0～+ 0～+ 0～+ 0～+ 0～+

- - - - - -

- - - - - -

Claims (10)

1, a kind of stable injection of palonosetron comprises:

A) 0.00001 to 0.0099mg/ml palonosetron or its pharmaceutically acceptable salt; With

B) pharmaceutically acceptable carrier.

2, the described injection of claim 1, wherein palonosetron or its pharmaceutically acceptable salt concentration are 0.0001 to 0.0099mg/ml.

3, the described injection of claim 1, wherein palonosetron or its pharmaceutically acceptable salt concentration are 0.0025mg/ml.

4, the described injection of claim 1, wherein pH value is 3.0-8.0.

5, the described injection of claim 1, wherein pH value is 6.0-8.0.

6, the described injection of claim 1, wherein pH value is 6.5-7.5.

7, the described injection of claim 1, wherein osmotic pressure regulator is selected from glucose or sodium chloride.

8, the described injection of claim 1, wherein antioxidant is selected from a kind of, two or more the mixture of sodium pyrosulfite, sodium sulfite, sodium sulfite, sodium thiosulfate and ascorbic acid.

9, the described injection of claim 1, wherein antioxidant is sodium sulfite or ascorbic acid.

10, the described injection of claim 1 charges into inert nitrogen gas or carbon dioxide.