CN102772427B - Compound polyethylene glycol electrolyte composition - Google Patents
Compound polyethylene glycol electrolyte composition Download PDFInfo
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- CN102772427B CN102772427B CN201210295717.4A CN201210295717A CN102772427B CN 102772427 B CN102772427 B CN 102772427B CN 201210295717 A CN201210295717 A CN 201210295717A CN 102772427 B CN102772427 B CN 102772427B
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Abstract
The invention relates to a compound polyethylene glycol electrolyte composition, and in particular relates to a composition containing polyethylene glycol and electrolyte. The composition comprises the following components: polyethylene glycol, potassium chloride, sodium bicarbonate and anhydrous sodium sulfate. According to 6000 parts of polyethylene glycol, the composition comprises 118-178 parts of sodium chloride, 60-90 parts of potassium chloride, 137-205 parts of sodium bicarbonate and 461-692 parts of anhydrous sodium sulfate. The composition disclosed by the invention has good pharmaceutical properties.
Description
Technical field
The present invention relates to field of medicaments, relate to a kind of Polyethylene Glycol and electrolytical compositions and its preparation method of comprising, particularly relate to a kind of polyethylene glycol-electrolyte powder and preparation method thereof.Said composition of the present invention can be used for treating constipation, feces infraction, faecal impaction, intestinal gas spasm, flatulence, also can be used for orthostatic lavage, colon cathartic or colon irrigating.
Background technology
Constipation is a kind ofly conventionally can cause uncomfortable common situation.Feces is trapped in colon and/or rectum can cause uncomfortable and headache.Under extreme case, in rectum, exist scybalum or argol piece can cause long constipation and dyschizia.
People have developed the Therapeutic Method of a lot of constipation, comprise diet control (for example: increase fiber content and the not edible food that is considered to cause constipation in food), cathartic and enema.Cathartic is the medicament that promotes and help relieving constipation.Infiltrative cathartic can make moisture be retained in colonic lumen, thereby offsets normal colon dehydration.By suppressing the dehydration of colon, that infiltrative cathartic can produce is more soft, volume is larger and the stream shape feces that is easier to discharge.
A lot of osmotic laxative treatments of using at present all comprise Polyethylene Glycol (PEG).Said composition can also comprise electrolyte.Movicol
be a on market on sale Polyethylene Glycol and the electrolytical cathartic of comprising.Movicol can be purchased from Norgine company limited (Chaplin House, Widewater Place, Moorhall Road, Harefield, Middlesex UB96NS, UK) in Britain and other countries.It takes on and sells with pouch, and every bag contains 13.8g powder.The composition of every bag is composed as follows: Macrogol (Polyethylene Glycol) 3350:13.125g; Sodium chloride: 350.7mg; Sodium bicarbonate: 178.5mg; Potassium chloride: 46.6mg; And flavouring agent and sweeting agent (trace).This is little also comprises instruction in packed, indicates the water of powder and 125mL is in harmonious proportion and is taken.
A lot of patients, when taking the cathartic of Powdered, graininess based on Polyethylene Glycol of Movicol or other, solution shape, suspension, can feel that mouthfeel is bad and too salty.These bad impressions can cause patient's resentment.
Before a lot of diagnosis and surgical operation, for example, before colonoscopy, barium enema examination or colonic operation, all need to carry out colon irrigating.Colon irrigating is also very effective for the postoperative infection that prevents low level intestinal.Colon irrigating is also considered to colon and empties.
Method be an orthostatic lavage, by drinking or pouring into a large amount of electrolyte by nasal feeding tube.This enema is also considered to intestinal or digestive tract cleanout fluid.Take in this solution and can cause bringing out property of body fluid diarrhoea, thereby reach the object of cleaning colon.Most of conventional enema all comprise Polyethylene Glycol.1980, Davis and he's colleague reported a kind of progress of enema, and as described in them, this enema is (the Davis GR.et al. linking together with micro-water and electrolytical absorption or secretion, Gastroenterology, 1980,78,991-995).This solution comprises sodium sulfate and Polyethylene Glycol.As described in the people such as Davis, this solution is except comprising sodium sulfate (40.0mM, 5.68g/L) and Polyethylene Glycol (PEG4000 " carbowax ", 64g/L) in addition, also comprise sodium chloride (25mM, 1.463g/L), potassium chloride (10mM, 0.745g/L), sodium bicarbonate (20mM, 1.680g/L) and water.The taking dose of this solution is 4 liters, and very effective to cleaning gastrointestinal tract.A kind of related solution is become commercialized, its trade name GoLYTELY
(Braintree Laboratories Inc, Braintree, Massachusetts, U.S.A.).
The commercial GoLYTELY starting selling in August, 1996
compositions is dry powdered, comprise sodium sulfate (40.0mM, 5.685g/L), sodium chloride (25mM, 1.464g/L), potassium chloride (10mM, 0.743g/L), sodium bicarbonate (20mM, 1.685g/L) and PEG3350 Polyethylene Glycol (59g/L), and be watered to 4 liters.GoLYTELY
also with the form of aqueous solution, sell.
With to take anti-constipation composition the same, patient takes GoLYTELY
or other cleanout fluid based on PEG are felt solution smell bad equally.These bad impressions can cause patient's resentment.
Faecal impaction or be called as feces and be detained and refer to that a large amount of feces is trapped in rectum or distal colon can not be unimpeded.The method that treatment feces is detained and the method for the above-mentioned constipation for the treatment of and colon irrigating are roughly the same, but conventionally, its dosage is larger than dosage required in the situation for the treatment of constipation.
Therefore, the therapy of a kind of Movicol of use of recommendation, for every day 8 pouch Movicol (every bag of amount that comprises composition as mentioned above) being dissolved in 1 premium on currency, was drunk in 6 hours, general maximum lasting 3 days.
As taken, other cathartics are the same with bowel relieving compositions, and a lot of patients are taking Movicol
or the compositions based on Polyethylene Glycol during faecal impaction, can be felt solution smell bad with treatment.These bad impressions can cause patient's resentment.Visible, comprise Polyethylene Glycol and electrolytical compositions is that people expect very much in the improvement of mouthfeel.
In addition, existing be used for the treatment of constipation, feces infraction, faecal impaction, intestinal gas spasm, flatulence, orthostatic lavage, colon cathartic or colon irrigating comprise Polyethylene Glycol and electrolytical compositions contains more Polyethylene Glycol conventionally, and electrolyte ratio is considerably less comparatively speaking.For example typically the Polyethylene Glycol of 1 weight fraction is approximately 0.05-0.5 weight portion corresponding to electrolytical total amount, particularly 0.1-0.2 weight portion.In the case, need to be to electrolytical amount special concern, for example in process of production, in transporting procedures, in disposal process, in use procedure, for whole preparation, electrolytical variation is to need especially to pay close attention to.
Summary of the invention
The object of the invention is the defect for above-mentioned one or more aspects, a kind of Polyethylene Glycol and electrolytical compositions of comprising is provided, phase etc. its there are following one or more advantages: have good mouthfeel, electrolyte has for example shelf stabilities of good pharmaceutical property in the processes such as production, storing, disposal, use.The inventor finds that the compositions with formula of the present invention has at least one above-mentioned advantage, has completed the present invention therefrom.
For this reason, first aspect present invention provides and has comprised Polyethylene Glycol and electrolytical compositions, comprises following component: Polyethylene Glycol, sodium chloride, potassium chloride, sodium bicarbonate, anhydrous sodium sulfate in said composition.The present composition can be Powdered, graininess, by Powdered through adding graininess that binding agent or wetting agent make, by the forms such as bulk Powdered or that graininess is pressed into.
According to the compositions of first aspect present invention, in the Polyethylene Glycol of every 6000 weight portions, the amount of sodium chloride is wherein 118-178 part, preferred 133-163 part, for example approximately 148 parts.
According to the compositions of first aspect present invention, in the Polyethylene Glycol of every 6000 weight portions, the amount of potassium chloride is wherein 60-90 part, preferred 67-83 part, for example approximately 75 parts.
According to the compositions of first aspect present invention, in the Polyethylene Glycol of every 6000 weight portions, the amount of sodium bicarbonate is wherein 137-205 part, preferred 154-188 part, for example approximately 171 parts.
According to the compositions of first aspect present invention, in the Polyethylene Glycol of every 6000 weight portions, the amount of anhydrous sodium sulfate is wherein 461-692 part, preferred 520-635 part, for example approximately 577 parts.
According to the compositions of first aspect present invention, wherein comprise the component of following weight portion:
| polyethylene Glycol | 6000 parts, |
| sodium chloride | 118-178 part, |
| potassium chloride | 60-90 part, |
| sodium bicarbonate | 137-205 part, |
| anhydrous sodium sulfate | 461-692 part. |
According to the compositions of first aspect present invention, wherein comprise the component of following weight portion:
| polyethylene Glycol | 6000 parts, |
| sodium chloride | 133-163 part, |
| potassium chloride | 67-83 part, |
| sodium bicarbonate | 154-188 part, |
| anhydrous sodium sulfate | 520-635 part. |
According to the compositions of first aspect present invention, wherein comprise the component of following weight portion:
| polyethylene Glycol | 6000 parts, |
| sodium chloride | approximately 155 parts, |
| potassium chloride | approximately 80 parts, |
| sodium bicarbonate | approximately 165 parts, |
| anhydrous sodium sulfate | approximately 570 parts. |
According to the compositions of first aspect present invention, wherein comprise the component of following weight portion:
| polyethylene Glycol | 6000 parts, |
| sodium chloride | approximately 148 parts, |
| potassium chloride | approximately 75 parts, |
| sodium bicarbonate | approximately 171 parts, |
| anhydrous sodium sulfate | approximately 577 parts. |
According to the compositions of first aspect present invention, wherein comprise the component of following weight portion:
| polyethylene Glycol | 6000 parts, |
| sodium chloride | approximately 140 parts, |
| potassium chloride | approximately 70 parts, |
| sodium bicarbonate | approximately 175 parts, |
| anhydrous sodium sulfate | approximately 585 parts. |
According to the compositions of first aspect present invention, wherein said Polyethylene Glycol has 2600 ~ 3400 mean molecule quantity (Mr).
According to the compositions of first aspect present invention, wherein said Polyethylene Glycol has 2600 ~ 3400 mean molecule quantity, and this mean molecule quantity is following mensuration:
The about 12.5g of taking polyethylene glycol test sample, accurately weighed, put in the dry withstand voltage conical flask of 200ml tool plug, add pyridine 25ml, heat and make to dissolve, let cool, precision adds the pyridine solution of phthalic anhydride (to get phthalic anhydride 14g, be dissolved in anhydrous pyridine 100ml, placement is spent the night, standby) 25ml, shake up, put in 98 ± 2 ℃ of boiling water baths, heat 30～60 minutes, take out cooling, precision adds sodium hydroxide volumetric solution (0.5mol/L) 50ml, the pyridine solution (1 → 100) of phenolphthalein of take is indicator, with sodium hydroxide volumetric solution (0.5mol/L), be titrated to aobvious red, and the result of titration is proofreaied and correct with blank assay.For the product of examination amount (g) and 4000, divided by (in titration process), consume the volume (ml) of sodium hydroxide volumetric solution (0.5mol/L), obtain the mean molecule quantity of test sample.
According to the compositions of first aspect present invention, wherein said Polyethylene Glycol has 2600 ~ 3200 mean molecule quantity.
According to the compositions of first aspect present invention, it has 2600 ~ 3400 correction PEG molecular weight (cMr).
According to the compositions of first aspect present invention, it has 2600 ~ 3400 correction PEG molecular weight, and this correction PEG molecular weight is following mensuration:
Get the about 12.5g (M of present composition test sample, unit is gram), accurately weighed, put in the dry withstand voltage conical flask of 200ml tool plug, add pyridine 25ml, heat and make to dissolve, let cool, precision adds the pyridine solution of phthalic anhydride (to get phthalic anhydride 14g, be dissolved in anhydrous pyridine 100ml, placement is spent the night, standby) 25ml, shake up, put in 98 ± 2 ℃ of boiling water baths, heat 30～60 minutes, take out cooling, precision adds sodium hydroxide volumetric solution (0.5mol/L) 50ml, the pyridine solution (1 → 100) of phenolphthalein of take is indicator, with sodium hydroxide volumetric solution (0.5mol/L), be titrated to aobvious red, read the volume (V of the sodium hydroxide volumetric solution consuming in this titration process, unit is milliliter), and the result of titration is proofreaied and correct with blank assay.With following formula (I), calculate the correction PEG molecular weight of present composition test sample:
It should be noted that, in the formula due to the present composition, contain other material, the weight effect that these materials produce PEG; Therefore in above formula (I), f be composition total weight divided by the value of the weight gained of contained Polyethylene Glycol in compositions, in the present invention, f can be described as the weight effect factor or correction factor or weight correction factor.Due to the weight effect of other material in the present composition, the effect positive divisor f of weight effect is between 1.129 ~ 1.194 on average, typically is f=1.162.For example, when f=1.162, can use the correction PEG molecular weight that calculates present composition test sample with following formula (II):
In the definition of above f being done, " f is that composition total weight is divided by the value of the weight gained of contained Polyethylene Glycol in compositions ", wherein " composition total weight except " can easily obtain, and it can be to the acquisition of directly weighing of compositions finished product; And " weight of contained Polyethylene Glycol in compositions " can obtain from two approach, a kind of approach is the PEG content that compositions indicates, also have a kind of easy but accurately approach be directly by certain method, to measure and to obtain, for example by following HPLC method, measure the content that obtains PEG in compositions:
A: use high performance liquid chromatograph, chromatographic column is hydroxyl post; Get sodium chloride 0.036g, potassium chloride 0.018g, sodium bicarbonate 0.04g, sodium sulfate 0.137g, add water to 100ml, as saline solution; Get the solution that above-mentioned saline solution 40ml is diluted with water to 1000ml, as mobile phase; Use differential refraction detector; Detector temperature: 30 ℃.Number of theoretical plate should be not less than 2500, and separating degree should meet the requirements.
B: get composition sample appropriate (containing the about 60g of PEG), stable precision, puts in 1000ml measuring bottle, is dissolved in water, and is diluted to scale, shakes up, and the accurate 10ml that draws, puts in 500ml measuring bottle, adds water and is diluted to scale, shakes up, as need testing solution.Separately get PEG reference substance, add preparation mobile phase saline solution 20ml used, add water and be made into the reference substance solution that concentration is 1.18mg/ml; Precision measures reference substance solution and each 20 μ l injecting chromatographs of need testing solution, records chromatogram.By external standard method, with calculated by peak area, obtain.
According to the compositions of first aspect present invention, it has 2600 ~ 3200 correction PEG molecular weight.
According to the compositions of first aspect present invention, its more than 90% powder body can pass through 24 eye mesh screens.In one embodiment, more than 95% powder body of said composition can pass through 24 eye mesh screens.In one embodiment, more than 98% powder body of said composition can pass through 24 eye mesh screens.
According to the compositions of first aspect present invention, its more than 90% powder body can pass through 50 eye mesh screens.In one embodiment, more than 95% powder body of said composition can pass through 50 eye mesh screens.In one embodiment, more than 98% powder body of said composition can pass through 50 eye mesh screens.
According to the compositions of first aspect present invention, its more than 90% powder body can pass through 65 eye mesh screens.In one embodiment, more than 95% powder body of said composition can pass through 65 eye mesh screens.In one embodiment, more than 98% powder body of said composition can pass through 65 eye mesh screens.
According to the compositions of first aspect present invention, its more than 90% powder body can pass through 80 eye mesh screens.In one embodiment, more than 95% powder body of said composition can pass through 80 eye mesh screens.In one embodiment, more than 98% powder body of said composition can pass through 80 eye mesh screens.
According to the compositions of first aspect present invention, it is each material through pulverizing independently of one another or pulverizing through two or more combinations arbitrarily, and crosses aperture and be less than after 24 orders (be preferably less than 50 orders, be preferably less than 65 orders) sieve, through optionally mixing, obtain powdered composition.In one embodiment, said composition prepares by method described in the arbitrary embodiment of second aspect.
According to the compositions of first aspect present invention, wherein can also comprise flavoring agent, for example the powdered flavor of various fragrance.
According to the compositions of first aspect present invention, wherein can also comprise sweeting agent, for example aspartame, sucralose, acesulfame potassium.
According to the compositions of first aspect present invention, it is pharmaceutical preparation.In one embodiment, it is the medicine types such as powder, granule, tablet.
According to the compositions of first aspect present invention, wherein said Polyethylene Glycol has 45 ~ 65 hydroxyl value.
According to the compositions of first aspect present invention, wherein said Polyethylene Glycol has 45 ~ 65 hydroxyl value, and this hydroxyl value is that following method is measured: get m gram of (about 10g) sample, stable precision, is placed in the dry conical flask that reflux condenser has been installed; The phthalic acid anhydride solution that adds 25.0ml, whirlpool makes to dissolve, and under reflux condenser, ebuillition of heated 60min, cooling; First with 25ml pyridine and 25ml water, rinse condenser, then add the phenolphthalein solution of 1.5ml, with the titration of 1M sodium hydroxide volumetric solution, until produce faint pink (volumetric solution volume v1, ml); With blank assay, proofread and correct (volumetric solution volume v2, ml); Use following formula to calculate hydroxyl value:
The sample that is greater than 0.5% for water content, at 100-105 ℃ of dry 2h, then calculates hydroxyl value with dry product.
According to the compositions of first aspect present invention, wherein said Polyethylene Glycol has 45 ~ 60 hydroxyl value.
In addition, the inventor finds, although add 10% ~ 15% the electrolyte except Polyethylene Glycol of having an appointment in the present composition, yet deduct these electrolytical qualitative factors, be the weight effect factor or correction factor or weight correction factor f value mentioned above, compositions of the present invention and its PEG raw material have suitable hydroxyl value.Be that the present composition can and be considered f value with reference to the method for PEG raw material, can record the intrinsic specific hydroxyl value of said composition, can be described as in the present invention the correction hydroxyl value of compositions.In the present invention, hydroxyl value can represent by english abbreviation HV, and proofreading and correct hydroxyl value can represent with english abbreviation cHV.
According to the compositions of first aspect present invention, it has 45 ~ 65 correction hydroxyl value.
According to the compositions of first aspect present invention, it has 45 ~ 65 correction hydroxyl value, and this correction hydroxyl value is following mensuration: get m gram of (about 12g) sample, stable precision, is placed in the dry conical flask that reflux condenser has been installed; The phthalic acid anhydride solution that adds 25.0ml, whirlpool makes to dissolve, and under reflux condenser, ebuillition of heated 60min, cooling; First with 25ml pyridine and 25ml water, rinse condenser, then add the phenolphthalein solution of 1.5ml, with the titration of 1M sodium hydroxide volumetric solution, until produce faint pink (volumetric solution volume v1, ml); With blank assay, proofread and correct (volumetric solution volume v2, ml); Use following formula calculation correction hydroxyl value:
wherein f as described herein.
Second aspect present invention provides the method for preparing compositions described in first aspect present invention, it comprises the following steps: make each material through pulverizing or pulverize through any two or more combinations independently of one another, and cross aperture and be less than 24 orders and (be preferably less than 50 orders, preferably be less than 65 orders) sieve after, through optionally mixing, obtain powdered composition.
Second aspect present invention also provides the method for preparing compositions described in first aspect present invention, and it comprises the following steps:
Make each material through pulverizing or pulverize through any two or more combinations independently of one another;
Through the material of pulverizing, cross aperture and be less than 24 orders (be preferably less than 50 orders, be preferably less than 65 orders) sieve;
Optionally the material of each pulverizing is mixed;
Mixing or unmixing each material are joined in packing container independently or together, obtain powdered composition.
According to the method for second aspect present invention, it comprises the following steps:
A) sodium chloride, potassium chloride, sodium bicarbonate, anhydrous sodium sulfate are pulverized independently of one another, or any two or more combinations in them are pulverized, then cross independently of one another or in combination aperture and be less than 24 orders (be preferably less than 50 orders, be preferably less than 65 orders) sieve;
B) Polyethylene Glycol is pulverized, then crossed aperture and be less than 24 orders (be preferably less than 50 orders, be preferably less than 65 orders) sieve;
C) step powder a) is mixed, obtain electrolyte mixed-powder;
D) make step c) electrolyte mixed-powder and step b) Polyethylene Glycol powder mix, then divide and install in packing container; Or electrolyte mixed-powder step c) and step b) Polyethylene Glycol powder divide and install in packing container successively or simultaneously independently, obtain powdered composition.
According to the method for second aspect present invention, it comprises the following steps:
A) make sodium chloride, potassium chloride, sodium bicarbonate, anhydrous sodium sulfate pulverize respectively and cross aperture and be less than 24 orders (be preferably less than 50 orders, be preferably less than 65 orders) sieve;
B) Polyethylene Glycol is pulverized, then crossed aperture and be less than 24 orders (be preferably less than 50 orders, be preferably less than 65 orders) sieve;
C) step powder a) is mixed by prescription proportioning, obtain electrolyte mixed-powder;
D) make step c) electrolyte mixed-powder and step b) Polyethylene Glycol powder mix, then divide and install in packing container, obtain powdered composition.
According to the method for second aspect present invention, it comprises the following steps:
A) make sodium chloride, potassium chloride, sodium bicarbonate, anhydrous sodium sulfate pulverize respectively and cross aperture and be less than 24 orders (be preferably less than 50 orders, be preferably less than 65 orders) sieve;
B) Polyethylene Glycol is pulverized, then crossed aperture and be less than 24 orders (be preferably less than 50 orders, be preferably less than 65 orders) sieve;
C) step powder a) is mixed by prescription proportioning, obtain electrolyte mixed-powder;
D) make step c) electrolyte mixed-powder and step b) Polyethylene Glycol powder divide and install in packing container successively or simultaneously independently, obtain powdered composition.
Arbitrary embodiment of applicable equally other the arbitrary embodiment of arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has or other either side, as long as they can be not conflicting, certainly, at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
Be further described to various aspects of the present invention below.
In the present invention, unless otherwise noted, % is the percent of w/w.
In the present invention, expression screen cloth specification can be used order, for example, in two notes on the use of version Chinese Pharmacopoeia in 2010, record, and for example 65 orders are corresponding to No. four sieves, and its sieve aperture internal diameter meansigma methods is 250 μ m ± 9.9 μ m.
In the present invention, phrase " more than 90% powder body can by 65 eye mesh screens " represents in every 100g powder have powder more than 90g can pass through 65 eye mesh screens, and the particle diameter of powder more than 90g is less than 250 μ m.
In the present invention, for modifying the term " nominal molecular weight " of Polyethylene Glycol, refer to the molecular weight that represents PEG molecular weight specification or model, two the 1243rd page of kinds of recording " Macrogol 4000 " of Pharmacopoeia of People's Republic of China version in 2010 for example, 4000 " nominal molecular weight " that are Polyethylene Glycol wherein.It should be noted that, above-mentioned nominal molecular weight is different with the mean molecule quantity of the Polyethylene Glycol of use the method for the invention practical measurement.
The Polyethylene Glycol using in the present invention has specific mean molecule quantity, for example, have 2600 ~ 3400 mean molecule quantity, preferably has 2600 ~ 3200 mean molecule quantity.This mean molecule quantity can be to measure according to following method: the about 12.5g of taking polyethylene glycol test sample, accurately weighed, put in the dry withstand voltage conical flask of 200ml tool plug, add pyridine 25ml, heat and make to dissolve, let cool, precision adds the pyridine solution of phthalic anhydride (to get phthalic anhydride 14g, be dissolved in anhydrous pyridine 100ml, placement is spent the night, standby) 25ml, shake up, put in 98 ± 2 ℃ of boiling water baths, heat 30～60 minutes, take out cooling, precision adds sodium hydroxide volumetric solution (0.5mol/L) 50ml, the pyridine solution (1 → 100) of phenolphthalein of take is indicator, with sodium hydroxide volumetric solution (0.5mol/L), be titrated to aobvious red, and the result of titration is proofreaied and correct with blank assay.For the product of examination amount (g) and 4000, divided by (in titration process), consume the volume (ml) of sodium hydroxide volumetric solution (0.5mol/L), obtain the mean molecule quantity of test sample.
In the present composition, having most of material is Polyethylene Glycol (Polyethylene Glycol account for composition total weight 86%), and a little is weakly alkaline sodium bicarbonate titration measuring PEG molecular weight is not had to impact (as calculated, the deviation of method measurement result impact being less than to 1%) substantially.Therefore, the present composition is measured by titration method described herein, still can effectively characterize the wherein feature of PEG molecular weight.Due to the weight effect of other material in the present composition, the effect positive divisor of weight effect is between 1.129 ~ 1.194 on average, typically is 1.162.At the present composition, can be similar to PEG molecular weight determination, after effect positive divisor is calculated, said composition has the typical PEG of a correction molecular weight, has defined thus " proofreading and correct PEG molecular weight " of the present invention for this reason.
Thus, the present composition has specific correction PEG molecular weight, and particularly, the present composition has 2600 ~ 3400 correction PEG molecular weight, preferably has 2600 ~ 3400 correction PEG molecular weight.This correction PEG molecular weight can be measured according to following method:
Get the about 12.5g (M of present composition test sample, unit is gram), accurately weighed, put in the dry withstand voltage conical flask of 200ml tool plug, add pyridine 25ml, heat and make to dissolve, let cool, precision adds the pyridine solution of phthalic anhydride (to get phthalic anhydride 14g, be dissolved in anhydrous pyridine 100ml, placement is spent the night, standby) 25ml, shake up, put in 98 ± 2 ℃ of boiling water baths, heat 30～60 minutes, take out cooling, precision adds sodium hydroxide volumetric solution (0.5mol/L) 50ml, the pyridine solution (1 → 100) of phenolphthalein of take is indicator, with sodium hydroxide volumetric solution (0.5mol/L), be titrated to aobvious red, read the volume (V of the sodium hydroxide volumetric solution consuming in this titration process, unit is milliliter), and the result of titration is proofreaied and correct with blank assay.With following formula, calculate the correction PEG molecular weight of present composition test sample:
For example f is the value between 1.129 ~ 1.194, for example f=1.162.
In the present invention, Polyethylene Glycol used has been used many decades at pharmaceutical industry, and extensive stock product and production technology are well known to those skilled in the art.The present invention's Polyethylene Glycol used can be that business is buied, and can also synthesize according to those skilled in the art's existing knowledge, or can synthesize with reference to prior art.For example, in the Polyethylene Glycol of the different size that each version Chinese Pharmacopoeia records, recorded its preparation method, for example, by forming with oxirane and water polycondensation.Again for example, CN1890291A discloses preparation and has had low formaldehyde content Polyethylene Glycol, although only provide instantiation to prepare molecular weight approximately 200 in this patent documentation, yet it will be apparent to those skilled in the art that the Polyethylene Glycol that can easily prepare desired molecular weight by changing the inventory of oxirane.Again for example, Zhao Zhexun (preparation of Polyethylene Glycol and application thereof, Tianjin Business College journal, 1993,13 (1): a kind of method that 18-21) discloses synthesizing polyethylene glycol, specific as follows: in rustless steel autoclave, first to add the solid base of ethylene glycol and pulverizing, stirring and dissolving, heat temperature raising, vacuum dehydration, in the time of 120 ℃, water is all to the greatest extent de-, and time nitrogen makes up the number.Guarantee in still, without after air, to pass into oxirane, be incubated 130 ~ 135 ℃, pressure 0.5 ~ 0.8MPa, reacts.While reaching proportional quantity Deng the amount of ethylene oxide passing into, (Polyethylene Glycol of synthetic different molecular weight has different proportional quantities), stops passing into (passing into 10 ~ 12 hours time), and still internal pressure is landed automatically.When approaching normal pressure, be cooled to 100 ~ 110 ℃, under stirring, add acetic acid to be neutralized to neutrality, discharging obtains finished product.In addition, the Yu Jiankun of Liming chemical Inst of the Ministry of Chemical Industry (Luoyang) (uses the research of alkaline-earth metal catalyst synthesizing polyethylene glycol at its document, Surfactant Industry, the 4th phase in 1994, a kind of synthetic method with the PEG of Narrow Molecular Weight Distribution is disclosed 38-42 page), specific as follows: in the flask of 250ml, to add 8 hydronium(ion)s of accurate-metering to be oxidized boron (Ba (OH)
28H
2o) with in advance through double distilled diglycol, on magnetic agitation heater in the oil bath of 90 ℃ evacuation dehydration 2 hours, weigh after cooling, add the phosphoric acid (H of metering
3pO), then vacuum dehydration 1 hour, until reach theoretical water removal with the metering of decrement method.While hot the initiator making is added 3L to control in still, under stirring, be warming up to 100 ℃, after evacuation, fill nitrogen, repeatedly three times above with air in Ex-all still, keep still internal pressure 0.25 ~ 0.5MPa, start to drip the oxirane (noting: its consumption can suitably be adjusted according to the Polyethylene Glycol finished product molecular weight of desired design) of processing through full gear, with recirculated cooling water, remove in time reaction liberated heat, control reaction temperature and be no more than 120 ℃, until the oxirane of metering adds.Be warming up to 130 ℃, then react 1 hour, cooling, evacuation, blowing.Aqueous sulfuric acid with 0.5% is neutralized to and is neutral, and heating ageing, filter, section, and packing, obtains Polyethylene Glycol finished product.In the present invention's specific embodiment below, as do not indicated in addition, Polyethylene Glycol used is substantially with reference to the disclosed method of sword elder brother the suitable adjustment process parameter Polyethylene Glycol that particularly oxirane ratio obtains, it has concrete specified mean molecule quantity according to the present invention titration measuring mentioned above, has also used for reference the content that method that CN1890291A records reduces formaldehyde in end-product in preparation process.
In the present invention, phrase " each material is through pulverizing independently of one another or through two or more combination pulverizing arbitrarily; also cross aperture and be less than 24 orders (being preferably less than 50 orders; be preferably less than 65 orders) sieve ", represent that various materials can pulverize separately individually, also any two kinds or more kinds of mixing wherein can be pulverized; Or sieve respectively after pulverizing respectively separately, after also can pulverizing respectively separately, (mixedly) sieves together, any two kinds or more kinds of mixing after pulverizing wherein can also be sieved the mixture of this pulverizing again.
In the present invention, phrase " is crossed aperture and is less than 24 orders (being preferably less than 50 orders; be preferably less than 65 orders) sieve " and represents that it is the sieve (it is the sieve that internal diameter is less than 355 μ m that preferred powder body can be less than 50 orders by sieve aperture internal diameter, and it is the sieve that internal diameter is less than 250 μ m that preferred powder body can be less than 65 orders by sieve aperture internal diameter) that internal diameter is less than 850 μ m that corresponding powder body can be less than 24 orders by sieve aperture internal diameter.
In addition, those skilled in the art know that, although the impurity in raw material is the low scope that is controlled at as far as possible, yet the inventor finds, in the present invention's Polyethylene Glycol raw material used, when its aldehyde type impurities, for example content of formaldehyde is lower than 20ppm during particularly lower than 15ppm, and the present composition has beat all pharmaceutical property.Therefore,, according to the compositions of first aspect present invention, in wherein said Polyethylene Glycol raw material, the content of aldehyde type impurities is lower than 20ppm, preferably lower than 15ppm, preferably lower than 10ppm.In one embodiment, described aldehyde type impurities is formaldehyde.In one embodiment, described formaldehyde impurity is following mensuration: get PEG raw material test sample 1.00g, and accurately weighed, add 0.6% sodium chromotropate solution 0.25ml, after cooling in frozen water, add 5.0ml sulphuric acid, shake up, standing 15 minutes, slowly quantitatively be transferred in the 25ml measuring bottle that fills 10ml water, let cool, slowly add water to scale, shake up, as need testing solution; Separately get formaldehyde 0.860g, accurately weighed, put in 100ml measuring bottle, be diluted with water to scale, precision measures 1ml, adds water and is quantitatively diluted to 100ml, and precision measures 1ml, from " adding 0.6% sodium chromotropate solution 0.25ml ", with method operation, solution, is 30ppm in contrast; In addition, can suitably reduce the contrast solution of the preparation of the formaldehyde amount of taking 25ppm, 20ppm, 15ppm, 10ppm etc.; Get above-mentioned two kinds of solution, according to ultraviolet visible spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2010), at 567nm wavelength place, measure absorbance, and use the blank solution of same method operation to proofread and correct; Need testing solution absorbance is lower than a certain concentration contrast solution, in this test sample formaldehyde amount lower than content of formaldehyde corresponding to this contrast solution.For example, when test sample absorbance is lower than contrast solution with the preparation of 0.860g formaldehyde, content of formaldehyde in test sample (FC) is lower than 30ppm.
In addition, the inventor finds, although add 10% ~ 15% the electrolyte except Polyethylene Glycol of having an appointment in the present composition, yet deduct these electrolytical qualitative factors, be the weight effect factor or correction factor or weight correction factor f value mentioned above, compositions of the present invention and its PEG raw material have suitable content of formaldehyde.Be that the present composition can and be considered f value with reference to the method for PEG raw material, can record the intrinsic specific content of formaldehyde of said composition, can be described as in the present invention the correction content of formaldehyde (cFC) of compositions.In the present invention, content of formaldehyde can represent by english abbreviation FC, and proofreading and correct content of formaldehyde can represent with english abbreviation cFC.
According to the compositions of first aspect present invention, the correction content of formaldehyde that it has lower than 20ppm, preferably has the correction content of formaldehyde lower than 15ppm, preferably has the correction content of formaldehyde lower than 10ppm.This correction content of formaldehyde is following mensuration:
Get present composition test sample appropriate (being approximately same as f * 1.00g), accurately weighed, add 0.6% sodium chromotropate solution 0.25ml, cooling in frozen water after, add 5.0ml sulphuric acid, shake up, standing 15 minutes, be slowly quantitatively transferred in the 25ml measuring bottle that fills 10ml water, let cool, slowly add water to scale, shake up, as need testing solution; Separately get formaldehyde 0.860g, accurately weighed, put in 100ml measuring bottle, be diluted with water to scale, precision measures 1ml, adds water and is quantitatively diluted to 100ml, and precision measures 1ml, from " adding 0.6% sodium chromotropate solution 0.25ml ", with method operation, solution, is 30ppm in contrast; In addition, can suitably reduce the contrast solution of the preparation of the formaldehyde amount of taking 25ppm, 20ppm, 15ppm, 10ppm etc.; Get above-mentioned two kinds of solution, according to ultraviolet visible spectrophotometry (two appendix IV A of Chinese Pharmacopoeia version in 2010), at 567nm wavelength place, measure absorbance, and use the blank solution of same method operation to proofread and correct; Need testing solution absorbance is lower than a certain concentration contrast solution, in this test sample formaldehyde amount lower than content of formaldehyde corresponding to this contrast solution.For example, when test sample absorbance is lower than contrast solution with the preparation of 0.860g formaldehyde, content of formaldehyde in test sample (FC) is lower than 30ppm.Wherein f as described herein.The inventor finds that other electrolytical existence in compositions does not affect the mensuration of compositions content of formaldehyde.
In the present invention, the Polyethylene Glycol of use and sodium chloride, potassium chloride, sodium bicarbonate, anhydrous sodium sulfate and other optional material such as powdered flavor, aspartame etc., they are food stage independently of one another; Preferably, they are pharmaceutical grade independently of one another.In addition, these materials can be homemade, also can buy from the market, food and the above-mentioned material with pharmaceutical grade all can easily buy from the market.
Although the present invention is to provide a kind of pulverous compositions, it can be called powder in some embodiments.Yet preferably, powdered composition of the present invention for example, is wrapped or is encapsulated in packing container with unit dosage form (1,1/2,1/3,1/4 times of amount of each consumption), in containers such as plastic bottle, vial, plastic bag, aluminium foil bag, particularly preferably be wrapped or be encapsulated in the plastic bag, aluminium foil bag of the types such as polyester, polyethylene, be more particularly preferably wrapped or be encapsulated in aluminium foil bag.The compound membrane bag of being made by composite having every wet trapping of extensive stock is also preferred.
In one embodiment of the invention, the polyethylene glycol-electrolyte powder providing is to be prepared by the method for following steps: two kinds of chlorates, a kind of carbonate and a kind of sulfate and other the optional flavoring agent except Polyethylene Glycol and/or sweeting agent are mixed to get to inorganic salt raw material mixture, then by inorganic salt raw material mixture and Polyethylene Glycol PEG with two charging utensils respectively charging divide and install in a packaging bag.
The inventor finds that the compositions with special formulation of the present invention has beat all effect as described in the present invention.
The specific embodiment
Below by specific embodiment/experimental example, further illustrate the present invention, still, should be understood to, these embodiment and experimental example are only used for the use specifically describing more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention used, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and operational approach are well known in the art.
In the compositions obtaining below, can seal with plastic bag or aluminium foil bag, the amount of every bag of packing is not particularly limited, for example, in PEG amount, can be 20-200 gram.Unless otherwise noted, the compositions below obtaining seals with aluminium foil bag, and the amount of every bag of packing can be 60.00 grams in PEG amount.In embodiment below, the mean molecule quantity (Mr) that raw materials used Polyethylene Glycol is dated, obtains according to titration measuring mentioned above.In example below, prepared compositions, through titration measuring mentioned above, has dated correction PEG molecular weight (cMr).
embodiment 1: prepare compositions of the present invention
Formula (preparing in every batch of total material 10kg):
| Polyethylene Glycol (Mr=3050, HV=55) | 6000 parts, |
| Sodium chloride | 155 parts, |
| Potassium chloride | 80 parts, |
| Sodium bicarbonate | 165 parts, |
| Anhydrous sodium sulfate | 570 parts, |
Method for making: Polyethylene Glycol is pulverized and crossed 50 mesh sieves, 65 mesh sieves are pulverized respectively and crossed to all the other each materials, and be dried 2 hours at 40-45 ℃; By sodium chloride, potassium chloride, sodium bicarbonate, anhydrous sodium sulfate mix homogeneously, obtain electrolyte mixture; Again this electrolyte mixture is substantially gone up by equivalent incremental method and mixed homogeneously with Polyethylene Glycol, obtain compositions of the present invention, encapsulation.
embodiment 2: prepare compositions of the present invention
Formula (preparing in every batch of total material 10kg):
| Polyethylene Glycol (Mr=2800, HV=59) | 6000 parts, |
| Sodium chloride | 148 parts, |
| Potassium chloride | 75 parts, |
| Sodium bicarbonate | 171 parts, |
| Anhydrous sodium sulfate | 577 parts, |
Method for making: with embodiment 1.
embodiment 3: prepare compositions of the present invention
Formula (preparing in every batch of total material 10kg):
| Polyethylene Glycol (Mr=3100, HV=53) | 6000 parts, |
| Sodium chloride | 140 parts, |
| Potassium chloride | 70 parts, |
| Sodium bicarbonate | 175 parts, |
| Anhydrous sodium sulfate | 585 parts, |
Method for making: will be mixed to get inorganic salt raw material mixture through pulverizing and cross 80 object sodium chloride, potassium chloride, sodium bicarbonate, anhydrous sodium sulfate, again by inorganic salt raw material mixture with through pulverizing and cross two feed hoppers charging respectively for 65 object Polyethylene Glycol PEG, be packaged in a packaging bag, obtain.
embodiment 4: prepare compositions of the present invention
Formula (preparing in every batch of total material 10kg):
| Polyethylene Glycol (Mr=2600, HV=65) | 6000 parts, |
| Sodium chloride | 118 parts, |
| Potassium chloride | 90 parts, |
| Sodium bicarbonate | 137 parts, |
| Anhydrous sodium sulfate | 692 parts, |
Method for making: with embodiment 1, the compositions obtaining is Powdered.This powdered composition is granulation shape further, or can be by the Powdered graininess of making through adding binding agent or wetting agent, or can be by the forms such as bulk Powdered or that graininess is pressed into.
embodiment 5: prepare compositions of the present invention
Formula (preparing in every batch of total material 10kg):
Method for making: with embodiment 1, obtain mixture of powders, it can be used for test below.In addition, this mixture of powders is granulated with 90% ethanol moistening, be dried, obtain can be described as the finished medicament of granule, more than 90% particle of this granule can pass through 24 mesh sieves.
embodiment 6: prepare compositions of the present invention
Formula (preparing in every batch of total material 10kg):
Method for making: with embodiment 3.
embodiment 7: prepare compositions of the present invention
Formula (preparing in every batch of total material 10kg):
| Polyethylene Glycol (Mr=2950, HV=54) | 6000 parts, |
| Sodium chloride | 133 parts, |
| Potassium chloride | 83 parts, |
| Sodium bicarbonate | 154 parts, |
| Anhydrous sodium sulfate | 635 parts, |
Method for making: with embodiment 1.
The compositions that above prepared by each embodiment, except as otherwise noted, they are all Powdered, and more than 98% powder body of this powdered composition can pass through 24 eye mesh screens, and its more than 95% powder body can pass through 50 eye mesh screens.
Following comparative example has been prepared and has been comprised Polyethylene Glycol and electrolytical compositions, and said composition is Powdered thing, and its more than 95% powder body can pass through 50 eye mesh screens:
Comparative example 1: except the Polyethylene Glycol Mr=3500 using in formula, outside HV=42, the other the same as in Example 2.
Comparative example 2: except the Polyethylene Glycol Mr=3850 using in formula, outside HV=40, the other the same as in Example 2.
Comparative example 3: except the Polyethylene Glycol Mr=4350 using in formula, outside HV=35, the other the same as in Example 2.
Comparative example 4: except the Polyethylene Glycol Mr=2400 using in formula, outside HV=68, the other the same as in Example 2.
Comparative example 5: except the Polyethylene Glycol Mr=2150 using in formula, outside HV=71, the other the same as in Example 2.
Comparative example 6: except the Polyethylene Glycol Mr=1850 using in formula, outside HV=75, the other the same as in Example 2.
Comparative example 7: except the Polyethylene Glycol Mr=3600 using in formula, outside HV=41, other is with embodiment 6.
Comparative example 8: except the Polyethylene Glycol Mr=2150 using in formula, outside HV=71, other is with embodiment 6.
Comparative example 9: except the Polyethylene Glycol Mr=3600 using in formula, outside HV=41, other is with embodiment 7.
Comparative example 10: except the Polyethylene Glycol Mr=2150 using in formula, outside HV=71, other is with embodiment 7.
Comparative example 11: except the Polyethylene Glycol Mr=3350 using in formula, outside HV=50, the other the same as in Example 2.
test example 1: the stability test of compositions
Above each embodiment and comparative example preparation, pack with the compound membrane bag of gas and wet favorable sealing property respectively, and every packed amount is counted 60g with Polyethylene Glycol.Each sample is placed to August in the calorstat of 42 ℃, measure the bicarbonate radical percent change that each compositions is compared during with high-temperature treatment not after high-temperature treatment, calculating formula is as follows:
The content assaying method of bicarbonate radical in compositions is as follows:
Get compositions test sample appropriate (comprising the about 60g of PEG), accurately weighed, put in 1000ml measuring bottle, be dissolved in water, and be diluted to scale, shake up, as need testing solution; Accurate to draw above-mentioned solution 100ml, put in conical flask, methylate is red-and bromocresol green mixes 10 of indicator solutions, with hydrochloric acid volumetric solution (0.1mol/L), being titrated to solution is dark violet redness by green transition, boil 2 minutes, be cooled to room temperature, continue to be titrated to solution and become mulberry from green.Every 1ml hydrochloric acid volumetric solution (0.1mol/L) is equivalent to the HCO of 6.102mg
3.The percentage composition of bicarbonate radical in calculation composition thus.
Result shows, places after 8 months for 42 ℃, and the bicarbonate radical percent change of each example composition is all between 97.5% ~ 101.7%, and for example the bicarbonate radical percent change of embodiment 1,2,3 each compositionss is respectively 99.6%, 98.2%, 99.3%; And the bicarbonate radical percent change of comparative example 1,2,3,7,9,11 compositionss is all between 88.6% ~ 94.8%, for example the bicarbonate radical percent change of comparative example 1,2,3 each compositionss is respectively 89.5%, 94.8%, 91.5%.The bicarbonate radical percent change of comparative example 4,5,6,8,10 compositionss is all between 96.6% ~ 99.8%.The inventor is in other test, according to the method for embodiment 4, prepare the compositions (Mr=2630 of synthetic PEG wherein, HV=72), obtain comparative example 12 compositionss, also according to the method for embodiment 6, prepare the compositions (Mr=3380 of synthetic PEG wherein, HV=41), obtain comparative example 13 compositionss.The same method of compositions of comparative example 12 and comparative example 13 is placed after 8 months at 42 ℃, and bicarbonate radical percent change is respectively 92.6% and 93.9%.
The PEG raw material using in above each embodiment and comparative example, and compositions prepared therefrom, these PEG raw materials and compositions after measured, content of formaldehyde wherein all at 5ppm with below 10.0ppm.After measured, these samples are placed after 8 months at 42 ℃, compare with the sample without high-temperature treatment, PEG molecular weight is substantially constant or micro-ly have a reduction, PEG the change of molecular weight percent is in 98% ~ 101% scope (PEG the change of molecular weight percent is 42 ℃ and places 8 months molecular weight analytes and divided by high-temperature process molecular weight analyte not, be multiplied by the value of 100% gained) all.In four other tests, use formula and the PEG performance identical with embodiment 2, that different is the PEG that uses different batches to prepare, content of formaldehyde is wherein 17.5ppm ~ 20ppm, 20ppm ~ 22.5ppm, 22.5ppm ~ 25ppm, 25ppm ~ 27.5ppm, obtains four and comprises PEG and electrolytical compositions; Have been surprisingly found that, carry out equally 42 ℃ and place test in 8 months, the bicarbonate radical percent change of these four compositionss is between 84.8% ~ 90.3% (bicarbonate radical percent change is 42 ℃ and places 8 months sample bicarbonate radical amounts and divided by high-temperature process sample bicarbonate radical amount not, be multiplied by the value of 100% gained) all; PEG the change of molecular weight percent all, in 83% ~ 89% scope, particularly have been surprisingly found that, content of formaldehyde more bicarbonate radical and PEG the change of molecular weight larger.
test example 2: intestinal cleans clinical experimental study
The present invention uses the some compositions of preparation above to carry out clinical trial.Every kind of reagent, as a test group, arranges 20 ~ 24 adult male volunteers.Reagent: embodiment 1, embodiment 4 and embodiment 6 gained powder compositions; Comparative example 4, comparative example 5, comparative example 6, comparative example 8 and comparative example 10 gained powder compositions.Reagent compound method: get powder appropriate (PEG wherein comprising is equivalent to 60g), be mixed with the solution of 1 liter with water dissolution.Usage and dosage: be grown up and measure about 2-4 liter for 1 time, oral with the every 1 hour speed of approximately 1 liter, when becoming transparency liquid, discharge liquor can finish administration; Total dosage can not be over 4 liters.A situation arises for the total effective rate of statistics different tests group and untoward reaction.Result shows: the total effective rate of embodiment 1, embodiment 4,6 three test group of embodiment is all between 95 ~ 100%, and for example the total effective rate of embodiment 1 is 97.1%; The total effective rate 84.8% of comparative example 4, the total effective rate of comparative example 5, comparative example 8 and comparative example 10 is respectively 68.8%, 69.7% and 70.6%, and the total effective rate of comparative example 6 is 18.7%.Herein, in the clinical trial of carrying out in the polyethylene glycol electrolytes compositions of the PEG of the specific mean molecule quantity of the present invention preparation, it not only has good intestinal cleaning action, and does not demonstrate any side effect; Yet, unexpectedly show, all there is the untoward reaction of 1-2 example vomiting in each comparative example group, and 6 groups of untoward reaction that also occur a routine creeping chill of comparative example.
test example 3: the physicochemical property of the test present composition
Use the mean molecule quantity algoscopy of Polyethylene Glycol mentioned above, and for the correction PEG molecular weight determination method of compositions, measure respectively the mean molecule quantity of raw material PEG used in each embodiment or comparative example and the correction PEG molecular weight of each compositions.Use Polyethylene Glycol hydroxy value measuring method mentioned above, and for the correction hydroxy value measuring method of compositions, measure respectively the hydroxyl value of raw material PEG used in each embodiment or comparative example and the correction hydroxyl value of each compositions.Result shows, compositions for each embodiment and comparative example, it is proofreaied and correct the percent of PEG molecular weight for the mean molecule quantity of its raw material PEG and (proofread and correct PEG molecular weight divided by the mean molecule quantity of its raw material PEG between 97 ~ 103%, be multiplied by again 100%, the value of gained), for example the Mr of the raw material PEG of embodiment 1 is 3050, and the cMr of its compositions is 3070; Result also shows, compositions for each embodiment and comparative example, it is proofreaied and correct the percent of hydroxyl value for its raw material PEG hydroxyl value and also between 97 ~ 103%, (proofreaies and correct hydroxyl value divided by its raw material PEG hydroxyl value, be multiplied by again 100%, the value of gained), for example the hydroxyl value of the raw material PEG of embodiment 1 is 55, and the correction hydroxyl value of its compositions is 54.Show that latter two molecular weight and hydroxyl value difference are less before preparation compositions, can reflect by the compositions as end product that compositions prepares for example PEG kind of raw material type used.In addition, use the content of formaldehyde algoscopy of Polyethylene Glycol mentioned above, and for the correction content of formaldehyde algoscopy of compositions, measure respectively the content of formaldehyde of raw material PEG used in each embodiment or comparative example and the correction content of formaldehyde of each compositions.Result shows, for the compositions of each embodiment and comparative example, it proofreaies and correct the percent of content of formaldehyde for its raw material PEG content of formaldehyde between 98 ~ 103%.
Claims (1)
1. comprise Polyethylene Glycol and electrolytical compositions, the consisting of of active component in said composition: Polyethylene Glycol, sodium chloride, potassium chloride, sodium bicarbonate, anhydrous sodium sulfate; Wherein the ratio of each component is: polyethylene glycol 6000 weight portion, sodium chloride 118-178 weight portion, potassium chloride 60-90 weight portion, sodium bicarbonate 137-205 weight portion, anhydrous sodium sulfate 461-692 weight portion;
And described Polyethylene Glycol has 2600 ~ 3200 mean molecule quantity, and this Polyethylene Glycol has 45 ~ 60 hydroxyl value.
2. according to the compositions of claim 1, consisting of of active component wherein: polyethylene glycol 6000 weight portion, sodium chloride 133-163 weight portion, potassium chloride 67-83 weight portion, sodium bicarbonate 154-188 weight portion, anhydrous sodium sulfate 520-635 weight portion.
3. according to the compositions of claim 1, consisting of of active component wherein: polyethylene glycol 6000 weight portion, sodium chloride 155 weight portions, potassium chloride 80 weight portions, sodium bicarbonate 165 weight portions, anhydrous sodium sulfate 570 weight portions.
4. according to the compositions of claim 1, consisting of of active component wherein: polyethylene glycol 6000 weight portion, sodium chloride 148 weight portions, potassium chloride 75 weight portions, sodium bicarbonate 171 weight portions, anhydrous sodium sulfate 577 weight portions.
5. according to the compositions of claim 1, consisting of of active component wherein: polyethylene glycol 6000 weight portion, sodium chloride 140 weight portions, potassium chloride 70 weight portions, sodium bicarbonate 175 weight portions, anhydrous sodium sulfate 585 weight portions.
6. according to the compositions of claim 1 to 5 any one, it has 2600 ~ 3200 correction PEG molecular weight; Wherein said correction PEG molecular weight is following mensuration:
Get compositions test sample 12.5g, this weight is counted M, unit is gram, accurately weighed, put in the dry withstand voltage conical flask of 200ml tool plug, add pyridine 25ml, heat and make to dissolve, let cool, precision adds the pyridine solution 25ml of phthalic anhydride, shake up, put in 98 ± 2 ℃ of boiling water baths, heat 30～60 minutes, take out cooling, precision adds the sodium hydroxide volumetric solution 50ml of 0.5mol/L, the pyridine solution of the phenolphthalein that 1 → 100 mode of take is prepared is indicator, with the sodium hydroxide volumetric solution of 0.5mol/L, be titrated to aobvious red, read the volume of the sodium hydroxide volumetric solution consuming in this titration process, this volume is counted V, unit is milliliter, and the result of titration is proofreaied and correct with blank assay, with following formula (I), calculate the correction PEG molecular weight of said composition test sample:
In formula (I), f is that composition total weight is divided by the value of the weight gained of contained Polyethylene Glycol in compositions;
Wherein, the pyridine solution of described phthalic anhydride obtains according to following method preparation: get phthalic anhydride 14g, be dissolved in anhydrous pyridine 100ml, placement is spent the night, standby.
7. according to the compositions of claim 1 to 5 any one, its:
More than 90% powder body can pass through 24 eye mesh screens;
More than 90% powder body can pass through 50 eye mesh screens;
More than 90% powder body can pass through 65 eye mesh screens; Or
More than 90% powder body can pass through 80 eye mesh screens.
8. according to the compositions of claim 1, it has 45 ~ 65 correction hydroxyl value; Described correction hydroxyl value is following mensuration: get 12g sample, this weight is counted m gram, and stable precision is placed in the dry conical flask that reflux condenser has been installed; The phthalic acid anhydride solution that adds 25.0 ml, whirlpool makes to dissolve, and under reflux condenser, ebuillition of heated 60 min, cooling; First with 25 ml pyridines and 25 ml water, rinse condenser, then add the phenolphthalein solution of 1.5 ml, with the titration of 1M sodium hydroxide volumetric solution, until produce faint pink, it is ml that this volumetric solution volume is counted v1， unit; With blank assay, proofread and correct, this volumetric solution volume v2， unit is ml; Use following formula calculation correction hydroxyl value:
Wherein f is that composition total weight is divided by the value of the weight gained of contained Polyethylene Glycol in compositions.
9. according to the compositions of claim 1, it has the correction content of formaldehyde lower than 15ppm; This correction content of formaldehyde is following mensuration:
Get that to be equivalent to the test sample of f * 1.00 g appropriate, accurately weighed, add 0.6% sodium chromotropate solution 0.25 ml, cooling in frozen water after, add 5.0ml sulphuric acid, shake up, standing 15 minutes, be slowly quantitatively transferred in the 25ml measuring bottle that fills 10ml water, let cool, slowly add water to scale, shake up, as need testing solution; Separately get formaldehyde 0.860 g, accurately weighed, put in 100ml measuring bottle, be diluted with water to scale, precision measures 1 ml, adds water and is quantitatively diluted to 100ml, and precision measures 1ml, from " adding 0.6% sodium chromotropate solution 0.25 ml ", with method operation, solution, is 30 ppm in contrast; In addition, suitably reduce the contrast solution that the formaldehyde amount of taking is prepared 25 ppm, 20 ppm, 15 ppm, 10 ppm; Get above-mentioned two kinds of solution, according to the ultraviolet visible spectrophotometry of two appendix IV A of Chinese Pharmacopoeia version in 2010, at 567nm wavelength place, measure absorbance, and use the blank solution of same method operation to proofread and correct; Need testing solution absorbance, lower than a certain concentration contrast solution, is proofreaied and correct content of formaldehyde lower than content of formaldehyde corresponding to this contrast solution in this test sample;
Wherein f is that composition total weight is divided by the value of the weight gained of contained Polyethylene Glycol in compositions.
10. according to the compositions of claim 1, wherein also comprise flavoring agent.
11. according to the compositions of claim 10, and wherein said flavoring agent is powdered flavor.
12. according to the compositions of claim 1, wherein also comprises sweeting agent.
13. according to the compositions of claim 12, and wherein said sweeting agent is selected from aspartame, sucralose, acesulfame potassium.
14. according to the compositions of claim 1, and it is pharmaceutical preparation.
15. according to the compositions of claim 14, and wherein said pharmaceutical preparation is the medicine type of powder, granule or tablet.
16. prepare the method for compositions described in claim 1 to 15 any one, it comprises the following steps: make each material through pulverizing or pulverize through any two or more combinations independently of one another, and aperture is less than after 24 mesh sieves excessively, through optionally mixing, obtains powdered composition.
17. prepare the method for compositions described in claim 1 to 15 any one, and it comprises the following steps:
Make each material through pulverizing or pulverize through any two or more combinations independently of one another,
Through the material of pulverizing, cross aperture and be less than 24 mesh sieves,
Optionally the material of each pulverizing is mixed,
Mixing or unmixing each material are joined in packing container independently or together, obtain powdered composition;
Or it comprises the following steps:
A) sodium chloride, potassium chloride, sodium bicarbonate, anhydrous sodium sulfate are pulverized independently of one another, or any two or more combinations in them are pulverized, then cross aperture independently of one another or in combination and be less than 24 mesh sieves;
B) Polyethylene Glycol is pulverized, then crossed aperture and be less than 24 mesh sieves;
C) step powder a) is mixed, obtain electrolyte mixed-powder;
D) make step c) electrolyte mixed-powder and step b) Polyethylene Glycol powder mix, then divide and install in packing container; Or electrolyte mixed-powder step c) and step b) Polyethylene Glycol powder divide and install in packing container successively or simultaneously independently, obtain powdered composition.
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| ES2909386T3 (en) | 2012-09-11 | 2022-05-06 | Norgine Bv | Compositions comprising polyethylene glycol and alkali or alkaline earth metal sulfates for use as colon cleansing compositions |
| TR201912004A2 (en) * | 2019-08-07 | 2021-02-22 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A SAFE FORMULATION CONTAINING POLYETHYLENE GLYCOL |
| CN110613731A (en) * | 2019-09-29 | 2019-12-27 | 重庆健能医药开发有限公司 | Method for improving taste of compound polyethylene glycol electrolyte powder |
| CN111419871A (en) * | 2020-03-26 | 2020-07-17 | 北京哈三联科技有限责任公司 | Compound polyethylene glycol electrolyte granules and preparation method thereof |
| CN115040484B (en) * | 2022-05-20 | 2023-05-02 | 浙江和沐康医药科技有限公司 | Potassium chloride granules directly filled with powder and preparation method thereof |
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| CN1705494A (en) * | 2002-10-25 | 2005-12-07 | 诺金欧洲公司 | Colon cleansing compositions and methods |
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| CN1150021A (en) * | 1996-01-11 | 1997-05-21 | 李智军 | Bowel clearing agent |
| CN1705494A (en) * | 2002-10-25 | 2005-12-07 | 诺金欧洲公司 | Colon cleansing compositions and methods |
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