CN102247369A - Compound naproxen esomeprazole medicine composition and preparation method thereof - Google Patents
Compound naproxen esomeprazole medicine composition and preparation method thereof Download PDFInfo
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- CN102247369A CN102247369A CN 201110237741 CN201110237741A CN102247369A CN 102247369 A CN102247369 A CN 102247369A CN 201110237741 CN201110237741 CN 201110237741 CN 201110237741 A CN201110237741 A CN 201110237741A CN 102247369 A CN102247369 A CN 102247369A
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Abstract
The invention discloses a compound naproxen esomeprazole medicine composition and a preparation method thereof. The medicine composition is bilayer tablets which are prepared by uniformly mixing and then pressing esomeprazole-containing quick release granules (1) and naproxen-containing slow release granules (2), wherein the esomeprazole-containing quick release granules are taken as a quick release layer, the naproxen-containing slow release granules are taken as a slow release layer, and naproxen is in a basically amorphous form. The medicine composition is simple in prescription, has good stability and is suitable for long-term storage. The compound naproxen esomeprazole slow release tablets provided by the invention has the advantages that the aim that naproxen and esomeprazole have synergic effect in a human body, curative effect is obviously improved, adverse effect is obviously reduced, daily administration frequency is reduced, administration cost is reduced, administration compliance of a patient is improved, blood concentration of medicine can be controlled, and bioavailability is effectively improved, thus important economic value and social significance are achieved.
Description
Technical field
The present invention relates to field of medicaments, relate to a kind of compound recipe naproxen esomeprazole pharmaceutical composition and preparation method thereof specifically.
Background technology
Naproxen
English by name: Naproxen;
Chemistry is by name: (+)-(S)-2-methyl-6-methoxyl group-2-naphthalene acetic acid;
Physicochemical property: white or off-white color crystalline powder, almost odorless.Can in lipid material, dissolve, almost insoluble in low pH value water, and can be free at high pH value water soluble.This material is at the naproxen 1.6 to 1.8 of pH7.4 octanol/water partition coefficient;
Fusing point: 153 ℃;
Chemical formula: C
14H
14O
3
Molecular weight: 230.259 g/mol;
CAS number: 22204-53-1;
Chemical constitution:
Naproxen belongs to nonsteroidal anti-inflammatory analgetic, has stronger anti-inflammatory pain-stopping effect, and 1976, naproxen was run after fame with Naprosyn and begun to sell as prescription drugs in the U.S..1980, naproxen sodium went on the market in the U.S. with the title of Anaprox.It all is to sell as prescription drugs basically all over the world.FDA goes on the market as OTC in approval naproxen sodium in 1994, and commodity are called Aleve.In Australia, the naproxen of low dosage fractional pack ranks on the SUSDP, be used for heating and treatment of pain that a variety of causes causes clinically, and be usually used in treating diseases such as rheumatic arthritis, osteoarthritis, ankylosing spondylitis, tendinitis, neuralgia, ventilation, the acute attack stage that is particularly useful for above-mentioned disease also can be used for primary dysmenorrhea and medium and small postoperative pain relieving in addition.15 minutes plasma concentration reach peak value after the intravenous injection, and the half-life is 12-14 hour.This medicine is better than treatment to treatment of traumatic pain to the therapeutic effect of inflammatory pain.But common naproxen preparation needs oral 2-3 time on the one, a 0.2-0.3g, and medicining times is frequent, taking dose is also big, and is not only inconvenient, and needing to be better than composition fluctuations very big, produce so-called " peak valley " phenomenon, when promptly needing concentration high, may have side effects, even poison, when needing concentration to hang down, may reduce below the treatment concentration, just do not produce curative effect of medication yet, and such oral medicine preparation has certain damaging action to gastric mucosa after entering stomach, causes gastrointestinal upset.
Chinese patent CN02112765.4 discloses a kind of production method of naproxen slow releasing capsule.The present invention adopts and add hypromellose, sodium alginate, No. 3 resins of acrylic acid in the naproxen crude drug, mix homogeneously, acrylic acid No. 3 resins, ethyl cellulose, diethyl phthalates are dissolved in ethanol, the two mix homogeneously are granulated again, it is encapsulated to add Pulvis Talci after drying.
Chinese patent CN02137348.5 relates to a kind of preparation method of naproxen sodium release tablet.The present invention adopts polymer substance hypromellose (HPMC) as framework material, is active component with the naproxen sodium, adds a certain amount of rate of release regulator, makes analgesia, anti-inflammatory preparation naproxen sodium release sheet through the science design.
Chinese patent CN200510116713.5 discloses preparation method of multi-type superfine naproxen medcine granule, adopt reaction-crystallization method, its technical characterictic is: (1) adds or does not add surfactant in sodium hydrate aqueous solution, and then adding naproxen medicine, be mixed with the naproxen drug solution that contains 0.15 ~ 0.9g/100ml, surfactant is polyvinyl pyrrolidone or polyoxyethylene 20 sorbitan monooleate, and the concentration of surfactant in solution is 0.5 ~ 6.0g/100mL; (2) with the speed dropping of 0.5mL/min or the hydrochloric acid solution of disposable adding; (3) crystallization temperature is at 5 ℃ ~ 25 ℃; (4) obtain nanoscale or micron-sized naproxen drug particles, pattern is hexagon lamellar, bar-shaped, spherical, petal-shaped, needle-like, cube or cotton-shaped.
Chinese patent CN200810106515.4 relates to the compositions of a kind of containing (S)-(+)-naproxen and pharmaceutical salts thereof, it is to be active component with in (S)-(+)-naproxen or its pharmaceutical salts and pseudoephedrine hydrochloride, the codeine phosphate one or both, mixes the compositions that forms with pharmaceutical carrier.Said composition can be made into oral formulations, comprises solid preparations such as ordinary tablet, dispersible tablet, chewable tablet, slow releasing tablet, capsule, granule.
Esomeprazole magnesium trihydrate
English by name: Esomeprazole magnesium trihydrate;
Chemistry is by name: two (sulfinyl of 5-methoxyl group-2-[(S)-[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl]]-1H-benzimidazole-1-yl) the magnesium salt trihydrate;
Physicochemical property: it is degraded in acid medium rapidly, but it is stable under alkali condition.At pH value 6.8(relief area) in 25 ℃ 19 hours, 37 ℃ 8 hours.
Chemical formula: C
34H
42MgN
6O
9S
2
Molecular weight: 767.2
CAS number: 217087-09-7;
Chemical constitution:
Esomeprazole magnesium is the S-isomer of omeprazole, reduces gastric acid secretion by specific targeting mechanism, for keeping away the specific inhibitor of lipid pump in the cell.With using gastro oesophageal reflux disease (GORD); The treatment of erosive reflux esophagitis, the esophagitis patient who has cured places the long term maintenance treatment of recurrence, also is used for eradicating gastric ulcer, duodenal ulcer and preventing its recurrence with suitable antimicrobial therapy drug combination.
Chinese patent CN200810111831.0 discloses the dosage form of esomeprazole magnesium drop pill, solved the low deficiency of bioavailability of tablet, also set forth and be easy to generate unsettled phenomenon in its long term store, it is catabiosis, make that the medicine related substance increases under the long-term room temperature storage condition, reduce bioavailability, offset the superiority of drop pill.
Chinese patent CN200810228898.2 the invention discloses a kind of pipe esomeprazole magnesium esomeprazole magnesium injection liquid that can treat gastro oesophageal reflux disease (GORD).
Esomeprazole is the S isomer of omeprazole, is that first can be used for clinical proton pump inhibitor (PPI) individual isomer.It has not available materia medica of omeprazole raceme and clinical advantages.Compare with omeprazole, esomeprazole has higher with more consistent bioavailability, and area is also bigger under the plasma concentration time graph.Esomeprazole has higher specificity to the parietal cell sour environment, and gathering in this environment, activation and covalency suppress proton pump.The proton pump at other positions of human body does not reach the esomeprazole gathering and activates needed acidity.Esomeprazole is first PPI individual isomer, and its bioavailability is higher than omeprazole.It is also remarkable than other clinical available PPI that esomeprazole suppresses sour excretory effect, and therefore, it has clinical advantage.
On May 5th, 2010 message---a kind of mixing dosage tablet (commodity are called Vimovo, and the manufacturer is AstraZeneca and Pozen company) that contains extended release enteric solubility naproxen (naproxen) and quick-releasing type esomeprazole magnesium (esomeprazole magnesium) simultaneously of U.S. food Drug Administration (FDA) approved.
The mechanism of action:Proton pump inhibitor steroid antibiotic medicine
Pharmacological action: be the slow release prescription that a kind of NSAID adds a kind of proton pump inhibitor.After oral, esomeprazole is to be published in the harmonization of the stomach naproxen for the first time to be released the back at small intestinal.Along with twice administration every day, the naproxen amount reaches about 4-5 days steady statue.
Clinical trial:Two are at random, double-blind study, and the patient who compares gastric ulcer takes the sickness rate or the enteric naproxen of this product.Experimenter, these units need to estimate the condition of NSAID every day to be treatment at least 6 months, as if them at 50 years old, the history in 5 years, geographical sign or duodenal ulcer in the past.These studies show that, trade name Vimovo20/500 every days has reduced by 6 months cumulative gastric ulcer sickness rate significantly twice and compared 500 milligrams of enteric naproxens, twice of every day.
The compound preparation of this NSAID (non-steroidal anti-inflammatory drug) (NSAID)/proton pump inhibitor is applicable to the S﹠S of relief from osteoarthritis (osteoarthritis), rheumatoid arthritis (rheumatoid arthritis) and ankylosing spondylitis (ankylosing spondylitis), can reduce the gastric ulcer risk that causes because of NSAID simultaneously in the susceptible patient.The osteoarthritis NSAID such as naproxen commonly used treats, and nearly 2,700 ten thousand Americans suffer from this disease.According to the news that Astrazeneca AB issued, 50% more than the NSAID life-time service person risk with gastrointestinal ulceration is arranged.Chief Medical Technologist Howard doctor Hutchinson of AstraZeneca mentions in a corporate news Press release, " by a kind of independent pill; Vimovo can provide a kind of effective pain relief agents and a kind of Embedded ' proton pump inhibitor ', to be used for the treatment of arthritic with NSAID dependency gastric ulcer risk.”
This approval of FDA is based on the data from PN400-301 and two key researchs of 6 months by a definite date of PN400-302, these data show, with give 2 500mg enteric solubility naproxens every day and compare, the incidence rate that 2 uses every day naproxen/esomeprazole extended release sheet can reduce the gastric ulcer under the endoscopy (is respectively 4.1% to 23.1% and 7.1% to 24.3%; The P value of two researchs is all less than 0.001).Reported with use the relevant the most common adverse events (〉 5% of naproxen/esomeprazole) comprise erosive gastritis, dyspepsia, gastritis, diarrhoea, gastric ulcer, upper abdominal pain and nauseating.
This kind does not have administrative protection in China, the domestic producing and selling of still not having said preparation.Clinical data demonstrates this compound preparation significant superiority in clinical practice.External listing sample adopts naproxen is made label, and esomeprazole quantitatively is sprayed at the label outside, complicated process of preparation, and domestic realization difficulty is big, the equipment requirements height, cost increases.
In order to overcome above-mentioned defective, upright topic a kind of new preparation prescription of research of special decision and preparation technology satisfy domestic clinical application demand, plug a gap.
Summary of the invention
Key in technical field herein and describe paragraph.Purpose of the present invention just is according to existing adjuvant and working condition, guaranteeing to have lower production cost and simple preparation technology, be suitable under the prerequisite of large-scale industrial production, being necessary to work out a kind of suitable prescription forms and preparation technology, can produce compound recipe naproxen esomeprazole pharmaceutical composition, make compound recipe naproxen esomeprazole pharmaceutical composition have good bioavailability and stability of drug products.
Advantage of the present invention and effect are that production method is simple, and cost is low, and the preparation that makes can reach effective blood drug concentration very soon after taking medicine, and make the blood drug level held stationary, reduce taking dose, reduce side effect.The human bioavailability result of the test shows that naproxen peak concentration and paddy concentration change scope are littler than ordinary preparation, and fluctuating margin is little, and fluctuation speed is half of ordinary preparation.
The object of the present invention is to provide a kind of compound recipe naproxen esomeprazole pharmaceutical composition and preparation method thereof, it can overcome the deficiency of prior art, can control medicine blood drug level effectively, make drug level stable, and have high bioavailability, can improve clinical efficacy, reduce medicining times, can reach continual and steady clinical effectiveness, can also improve compliance, reduce untoward reaction.
Purpose of the present invention provides a kind of compound recipe naproxen esomeprazole pharmaceutical composition, it is characterized in that the prescription of making 1000 is composed as follows:
Immediate-release granules (1) contains:
Esomeprazole magnesium 20-40g(is in esomeprazole)
Lactose 50-100g
Meglumine 15-30g
Sodium hydroxide 0.5-1g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Slow-releasing granules (2) contains:
Naproxen 375-500g
Polyethylene glycol 6000 100-150g
Hypromellose K
15M100-200g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of.
Purpose of the present invention provides a kind of compound recipe naproxen esomeprazole pharmaceutical composition, it is characterized in that, immediate-release granules (1) and slow-releasing granules (2) are made up of the main ingredient of following weight proportion and are preferably in the described compound recipe naproxen esomeprazole:
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Immediate-release granules (1) contains:
Esomeprazole magnesium 20g(is in esomeprazole)
Lactose 50g
Meglumine 15g
Sodium hydroxide 0.5g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Slow-releasing granules (2) contains
Naproxen 375g
Polyethylene glycol 6000 100g
Hypromellose K
15M150g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of.
Purpose of the present invention provides a kind of compound recipe naproxen esomeprazole pharmaceutical composition, it is characterized in that, immediate-release granules (1) and slow-releasing granules (2) are made up of the main ingredient of following weight proportion and are preferably in the described compound recipe naproxen esomeprazole:
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Immediate-release granules (1) contains:
Esomeprazole magnesium 20g(is in esomeprazole)
Lactose 100g
Meglumine 30g
Sodium hydroxide 1g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Slow-releasing granules (2) contains:
Naproxen 500g
Polyethylene glycol 6000 100g
Hypromellose K
15M200g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of.
Another object of the present invention provides compound recipe naproxen esomeprazole preparation of drug combination method, be that esomeprazole and adjuvant are mixed and made into immediate-release granules (1), as release layer, with the hydrophilic gel matrix material polyethylene glycol 6000 with the naproxen of half recipe quantity make be ground into suitable granularity behind the solid dispersion granule again with the naproxen and the slow-release material hypromellose K of other half recipe quantity
15MThe granule that adopts binding agent to make suitable granularity behind the mix homogeneously is mixed and made into slow-releasing granules (2), as slow release layer; Make double-layer tablet with conventional method: it is characterized in that, the preparation process of described immediate-release granules (1) is: the esomeprazole sodium of recipe quantity is crossed 100 mesh sieves, then behind the meglumine and sodium hydroxide mix homogeneously with esomeprazole sodium and recipe quantity, add the abundant mixing of lactose again, 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent, add in batches and mix, make the soft material that is fit to granulation, cross 20 mesh sieve system wet granulars, dryly must do granule at 40 ℃, cross 20 mesh sieve granulate, make granule (1); The preparation process of described slow-releasing granules (2) is: adopt the spray drying mode to make amorphous form basically naproxen, and standby; Polyethylene glycol 6000 in 80 ℃ of fusions, is added the naproxen of half recipe quantity, and vigorous stirring becomes solid with the frozen water quenching then to evenly, crosses 20 mesh sieves, and granule was placed 2 hours in 0-4 ℃ of refrigerator, after 20 mesh sieves, promptly gets even-grained solid dispersion; The hypromellose of recipe quantity is crossed 100 mesh sieves; the naproxen that adds half recipe quantity then makes its abundant mix homogeneously; 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent; add in batches and mix, make and be fit to the soft material of granulating, cross 20 mesh sieve system wet granulars; dryly must do granule at 45-55 ℃; cross 20 mesh sieve granulate, solid dispersion granule and this granule mix homogeneously are made granule (2), adopt conventional preparation method to be pressed into double-layer tablet granule (1) and granule (2).
Compound recipe naproxen esomeprazole pharmaceutical composition of the present invention is characterized in that, is packaged in barrier material for example in aluminium foil foaming cover or polypropylene tube and the HDPE bottle.
Below by conceptual design and prescription screening explanation the present invention.
According to the clinical application characteristics and to the specific (special) requirements of two kinds of drug releasing rates, we analyze and study the physicochemical property of naproxen and esomeprazole.
Release under one's belt after naproxen is oral causes the stomach local concentration higher, cause untoward reaction such as calcination, and the naproxen metabolism is very fast, and the analgesic activity time is shorter.Also there is the peak valley phenomenon need concentration after oral in vivo, when peak concentration, occurs feeling sick, untoward reaction such as vomiting.In order effectively to control the blood drug level of medicine, make blood drug level stable, and have high bioavailability, improve clinical efficacy, reduce and take number of times, reach continual and steady analgesic effect, reduce untoward reaction, naproxen should be prepared into slow releasing preparation, make it continue to discharge.
Esomeprazole magnesium trihydrate is degraded rapidly in acid medium, but it is stable under alkali condition, at pH value 6.8(relief area) under 25 ℃ of situations, kept stability characteristic (quality) in 19 hours, under 37 ℃ of situations, kept stability characteristic (quality) in 8 hours.On selecting, adjuvant considers basic auxiliary.
At first, we carry out compatibility test to two kinds of raw materials and adjuvant, investigate the steadiness of each raw material.Choosing naproxen, esomeprazole magnesium trihydrate mixes by a certain percentage with adjuvant sodium hydroxide, meglumine respectively, get a certain amount of, test method according to influence factor in the medicine stability guideline, respectively under 4500LX ± 500LX illumination condition, in 60 ℃ of pyritous calorstats and 25 ℃ of relative humidity 92.5% ± 5%(KNO3 saturated solutions) calorstat placed 10 days, investigate appearance character and related substance, the results are shown in following table:
Shown that by above result of the test naproxen mixes by a certain percentage with basic auxiliary and places under influence factor's condition, compares with the naproxen raw material of independent placement, related substance obviously increases, instability; Esomeprazole magnesium trihydrate is mixed by a certain percentage with basic auxiliary and is placed under influence factor's condition, compare with the esomeprazole magnesium trihydrate raw material of independent placement, related substance is not seen obvious increase, can effectively suppress raw material degraded under illumination, high temperature, the super-humid conditions, and is comparatively stable; To sum up consider preparation stability selection double-layer tablet preparation technology.
On the basis to the relevant research of the supplementary material compatibility, the following several substantially reasonably prescriptions of design are so that launch screening and optimization.
Esomeprazole immediate-release granules (1) prescription screening
Preparation technology:
Prescription 1: the esomeprazole sodium of recipe quantity is crossed 100 mesh sieves, then with esomeprazole sodium and the abundant mixing of recipe quantity lactose, 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent, add in batches and mix, make and be fit to the soft material of granulating, cross 20 mesh sieve system wet granulars, dryly must do granule at 40 ℃, cross 20 mesh sieve granulate, regulate tablet machine, tabletting.
Prescription 2: the esomeprazole sodium of recipe quantity is crossed 100 mesh sieves, then behind the meglumine and sodium hydroxide mix homogeneously with esomeprazole sodium and recipe quantity, adding the abundant mixing of lactose again, is binding agent with 80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30, adds in batches and mixes, make the soft material that is fit to granulation, cross 20 mesh sieve system wet granulars, dryly must do granule, cross 20 mesh sieve granulate at 40 ℃, regulate tablet machine, tabletting.
Investigate the relevant parameter of respectively writing out a prescription:
Investigate a measurement result
The stripping curve measurement result
By above result of the test as can be known: the prescription 1 and the 2 stripping trend basically identicals of writing out a prescription, reached maximum stripping quantity at 45 minutes, trial-production prescription 1 character is an erotic film under the basic auxiliary environment not having, related substance obviously increases, it is all up to specification that the prescription of manufacturing experimently under the basic auxiliary environment 2 is respectively investigated index, still the 2 further screenings and optimizing of selecting to write out a prescription.
Naproxen slow-releasing granules (2) prescription screening
At first select through comminution by gas stream, do not pass through spray drying and spray-dired raw material, carry out the trial-production of naproxen prescription.
Preparation technology: polyethylene glycol 6000 in 80 ℃ of fusions, is added the naproxen of half recipe quantity, and vigorous stirring is to even, become solid with the frozen water quenching then, cross 20 mesh sieves, granule was placed 2 hours in 0-4 ℃ of refrigerator, after 20 mesh sieves, promptly get even-grained solid dispersion; Hypromellose K with recipe quantity
15MCross 100 mesh sieves; the naproxen that adds half recipe quantity then makes its abundant mix homogeneously; 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent; add in batches and mix, make and be fit to the soft material of granulating, cross 20 mesh sieve system wet granulars; dryly must do granule at 45-55 ℃; cross 20 mesh sieve granulate,, be pressed into the tablet of suitable hardness solid dispersion granule and this granule mix homogeneously.Investigate the relevant parameter of respectively writing out a prescription:
Investigate a measurement result
The release profiles measurement result
By above result of the test as can be known: prescription 3-writes out a prescription under the situation of 5 angle of reposes, character, hardness, the equal no significant difference of friability, and the releasing trend of prescription 5 obviously is better than writing out a prescription 3 and prescription 4, still the 5 further screenings and optimizing of selecting to write out a prescription.
Compound recipe naproxen esomeprazole sheet must prepare
Esomeprazole immediate-release granules (1)
The esomeprazole sodium of recipe quantity is crossed 100 mesh sieves, then behind the meglumine and sodium hydroxide mix homogeneously with esomeprazole sodium and recipe quantity, add the abundant mixing of lactose again, 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent, adds in batches and mixes, and makes to be fit to the soft material of granulating, cross 20 mesh sieve system wet granulars, dryly must do granule at 40 ℃, cross 20 mesh sieve granulate, make immediate-release granules (1).
Naproxen slow-releasing granules (2)
Preparation technology: polyethylene glycol 6000 in 80 ℃ of fusions, is added the naproxen of half recipe quantity, and vigorous stirring is to even, become solid with the frozen water quenching then, cross 20 mesh sieves, granule was placed 2 hours in 0-4 ℃ of refrigerator, after 20 mesh sieves, promptly get even-grained solid dispersion; Hypromellose K with recipe quantity
15MCross 100 mesh sieves; the naproxen that adds half recipe quantity then makes its abundant mix homogeneously; 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent; add in batches and mix, make and be fit to the soft material of granulating, cross 20 mesh sieve system wet granulars; dryly must do granule at 45-55 ℃; cross 20 mesh sieve granulate,, make slow-releasing granules (2) solid dispersion granule and this granule mix homogeneously.
After immediate-release granules (1) and slow-releasing granules (2) measured content respectively, it was heavy to calculate sheet according to the result, adopts conventional method to prepare double-layer tablet.Compound recipe naproxen esomeprazole sheet is placed glass dish, respectively at 4500LX ± 500 LX illumination, 60 ℃ ± 2 ℃, 25 ℃ relative humidity 75% ± 5%(NaCl saturated solutions) calorstat under placed 10 days, detect in sampling in 0,5,10 day:
Above result of the test as can be known, naproxen esomeprazole sheet is at 25 ℃ of relative humidity 75% ± 5%(NaCl saturated solutions) calorstat place 5 days sampling and measuring, the moisture absorption weightening finish is 5.9% greater than 5%, and is against regulation, do not carry out other mensuration, preparation guards against damp in storage.Adopt the better packaging material of humidity resistance to pack, avoid the mass discrepancy in storage; Naproxen esomeprazole sheet was placed 10 days in 4500LX ± 500 LX illumination, 60 ℃ ± 2 ℃ calorstat, and it is all up to specification that each detects index, and prescription is stable.So the big production scale of simulation with 10,000 every batch, is amplified and is produced 3 batches.
Through evidence: product formulation and technology simple possible, be packaged in 40 ℃ ± 2 ℃ through three batches of products with listing, placed under the accelerated test condition of relative humidity 75% ± 5% 6 months and the long term test condition was placed 6 months, the result shows, quality is more stable to meet production requirement.
Description of drawings
Fig. 1 compound recipe naproxen esomeprazole blade technolgy flow chart.
The specific embodiment
Below in conjunction with embodiment the present invention is described in further detail, but should understands the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Immediate-release granules (1) contains:
Esomeprazole magnesium 20g(is in esomeprazole)
Lactose 50g
Meglumine 15g
Sodium hydroxide 0.5g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Slow-releasing granules (2) contains
Naproxen 375g
Polyethylene glycol 6000 100g
Hypromellose K
15M150g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Preparation process:
1. the esomeprazole sodium of recipe quantity is crossed 100 mesh sieves, then behind the meglumine and sodium hydroxide mix homogeneously with esomeprazole sodium and recipe quantity, add the abundant mixing of lactose again, 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent, adds in batches and mixes, and makes to be fit to the soft material of granulating, cross 20 mesh sieve system wet granulars, dryly must do granule at 40 ℃, cross 20 mesh sieve granulate, make granule (1);
2. the preparation process of described slow-releasing granules (2) is: adopt the spray drying mode to make amorphous form basically naproxen, and standby; Polyethylene glycol 6000 in 80 ℃ of fusions, is added the naproxen of half recipe quantity, and vigorous stirring becomes solid with the frozen water quenching then to evenly, crosses 20 mesh sieves, and granule was placed 2 hours in 0-4 ℃ of refrigerator, after 20 mesh sieves, promptly gets even-grained solid dispersion; The hypromellose of recipe quantity is crossed 100 mesh sieves, the naproxen that adds half recipe quantity then makes its abundant mix homogeneously, 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent, add in batches and mix, make the soft material of be fit to granulating, cross 20 mesh sieve system wet granulars, dryly must do granule at 45-55 ℃, cross 20 mesh sieve granulate, solid dispersion granule and this granule mix homogeneously are made granule (2);
3. immediate-release granules (1) and slow-releasing granules (2) are measured content;
4. according to the assay result, regulate loading amount, the compacting double-layer tablet;
5. packing is put in storage, promptly.
Embodiment 2
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Immediate-release granules (1) contains:
Esomeprazole magnesium 20g(is in esomeprazole)
Lactose 100g
Meglumine 30g
Sodium hydroxide 1g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Slow-releasing granules (2) contains:
Naproxen 500g
Polyethylene glycol 6000 100g
Hypromellose K
15M200g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Preparation process: with embodiment 1.
Embodiment 3
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Immediate-release granules (1) contains:
Esomeprazole magnesium 40g(is in esomeprazole)
Lactose 50g
Meglumine 15g
Sodium hydroxide 0.5g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Slow-releasing granules (2) contains
Naproxen 375g
Polyethylene glycol 6000 100g
Hypromellose K
15M150g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Preparation process: with embodiment 1.
Embodiment 4
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Immediate-release granules (1) contains:
Esomeprazole magnesium 40g(is in esomeprazole)
Lactose 100g
Meglumine 30g
Sodium hydroxide 1g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Slow-releasing granules (2) contains:
Naproxen 500g
Polyethylene glycol 6000 100g
Hypromellose K
15M200g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Preparation process: with embodiment 1.
The comparative example 1
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Esomeprazole magnesium 20g(is in esomeprazole)
Lactose 100g
Meglumine 30g
Sodium hydroxide 1g
Naproxen 500g
Polyethylene glycol 6000 100g
Hypromellose K
15M200g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Preparation process:
1. naproxen is adopted the spray drying mode to make amorphous form basically, standby;
2. polyethylene glycol 6000 adds the naproxen of half recipe quantity in 80 ℃ of fusions, and vigorous stirring is to even, become solid with the frozen water quenching then, cross 20 mesh sieves, granule was placed 2 hours in 0-4 ℃ of refrigerator, after 20 mesh sieves, promptly get even-grained solid dispersion granule (1);
3. the esomeprazole sodium of recipe quantity is crossed 100 mesh sieves, then behind the meglumine and sodium hydroxide mix homogeneously with esomeprazole sodium and recipe quantity, add lactose, abundant mixing again, 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent, adds in batches and mixes, and makes to be fit to the soft material of granulating, cross 20 mesh sieve system wet granulars, dryly must do granule at 40 ℃, cross 20 mesh sieve granulate, make granule (2);
4. the hypromellose of recipe quantity is crossed 100 mesh sieves, the naproxen that adds half recipe quantity then makes its abundant mix homogeneously, 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent, add in batches and mix, make the soft material of be fit to granulating, cross 20 mesh sieve system wet granulars, dryly must do granule at 45-55 ℃, cross 20 mesh sieve granulate, solid dispersion granule and this granule mix homogeneously are made granule (3);
5. granule (1), granule (2) and granule (3) are measured content;
6. according to the assay result, behind granule (1), granule (2) and granule (3) mix homogeneously, regulate loading amount, tabletting;
7. packing is put in storage, promptly.
Test example 1
The long-term stable experiment result
Test example 2
The accelerated test stability result
Last table shows that comparative example's related substance of the present invention obviously increases, and quality is inferior to embodiment 1 and embodiment 2.The sample of the embodiment of the invention 1, embodiment 2 is comparatively stable, and it is qualified that each index detects.
Claims (9)
1. a compound recipe naproxen esomeprazole magnesium draws the azoles pharmaceutical composition, its described pharmaceutical composition be by as release layer contain esomeprazole immediate-release granules (1) and as the double-layer tablet that naproxen slow-releasing granules (2) is pressed into that contains of slow release layer.
2. pharmaceutical composition as claimed in claim 1, wherein naproxen is unbodied form basically.
3. pharmaceutical composition as claimed in claim 1, wherein immediate-release granules (1) comprises alkaline reagent, water-soluble diluent reaches randomly other excipient.
4. pharmaceutical composition as claimed in claim 3, wherein this alkaline reagent is selected alkali metal hydroxide, basic amino acid and meglumine.
5. pharmaceutical composition as claimed in claim 1 is characterized in that, immediate-release granules (1) and slow-releasing granules (2) are made up of the main ingredient of following weight proportion in the described compound recipe naproxen esomeprazole pharmaceutical composition:
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Immediate-release granules (1) contains:
Esomeprazole magnesium 20-40g(is in esomeprazole)
Lactose 50-100g
Meglumine 15-30g
Sodium hydroxide 0.5-1g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Slow-releasing granules (2) contains:
Naproxen 375-500g
Polyethylene glycol 6000 100-150g
Hypromellose K
15M100-200g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of.
6. compound recipe naproxen esomeprazole pharmaceutical composition as claimed in claim 1 is characterized in that, immediate-release granules (1) and slow-releasing granules (2) are made up of the main ingredient of following weight proportion in the described compound recipe naproxen esomeprazole:
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Immediate-release granules (1) contains:
Esomeprazole magnesium 20g(is in esomeprazole)
Lactose 50g
Meglumine 15g
Sodium hydroxide 0.5g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Slow-releasing granules (2) contains
Naproxen 375g
Polyethylene glycol 6000 100g
Hypromellose K
15M150g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of.
7. compound recipe naproxen esomeprazole pharmaceutical composition as claimed in claim 1 is characterized in that, immediate-release granules (1) and slow-releasing granules (2) are made up of the main ingredient of following weight proportion in the described compound recipe naproxen esomeprazole:
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Immediate-release granules (1) contains:
Esomeprazole magnesium 20g(is in esomeprazole)
Lactose 100g
Meglumine 30g
Sodium hydroxide 1g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of
Slow-releasing granules (2) contains:
Naproxen 500g
Polyethylene glycol 6000 100g
Hypromellose K
15M200g
80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30 is an amount of.
8. the described compound recipe naproxen of claim 1-7 esomeprazole preparation of drug combination method, be that esomeprazole and adjuvant are mixed and made into immediate-release granules (1), as release layer, with the hydrophilic gel matrix material polyethylene glycol 6000 with the naproxen of half recipe quantity make be ground into suitable granularity behind the solid dispersion granule again with the naproxen and the slow-release material hypromellose K of other half recipe quantity
15MThe granule that adopts binding agent to make suitable granularity behind the mix homogeneously is mixed and made into slow-releasing granules (2), as slow release layer; Make double-layer tablet with conventional method: it is characterized in that, the preparation process of described immediate-release granules (1) is: the esomeprazole sodium of recipe quantity is crossed 100 mesh sieves, then behind the meglumine and sodium hydroxide mix homogeneously with esomeprazole sodium and recipe quantity, add the abundant mixing of lactose again, 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent, add in batches and mix, make the soft material that is fit to granulation, cross 20 mesh sieve system wet granulars, dryly must do granule at 40 ℃, cross 20 mesh sieve granulate, make granule (1); The preparation process of described slow-releasing granules (2) is: adopt the spray drying mode to make amorphous form basically naproxen, and standby; Polyethylene glycol 6000 in 80 ℃ of fusions, is added the naproxen of half recipe quantity, and vigorous stirring becomes solid with the frozen water quenching then to evenly, crosses 20 mesh sieves, and granule was placed 2 hours in 0-4 ℃ of refrigerator, after 20 mesh sieves, promptly gets even-grained solid dispersion; The hypromellose of recipe quantity is crossed 100 mesh sieves; the naproxen that adds half recipe quantity then makes its abundant mix homogeneously; 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent; add in batches and mix; make the soft material that is fit to granulation; cross 20 mesh sieve system wet granulars; dryly must do granule at 45-55 ℃; cross 20 mesh sieve granulate; solid dispersion granule and this granule mix homogeneously are made granule (2), adopt conventional preparation method to be pressed into double-layer tablet immediate-release granules (1) and slow-releasing granules (2).
9. compound recipe naproxen esomeprazole pharmaceutical composition as claimed in claim 1 is characterized in that, is packaged in barrier material for example in aluminium foil foaming cover or polypropylene tube and the HDPE bottle.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115025087A (en) * | 2022-06-02 | 2022-09-09 | 吉林医药学院 | Preparation method of felodipine-naproxen co-amorphous drug system |
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| CN101249078A (en) * | 2008-03-25 | 2008-08-27 | 江苏奥赛康药业有限公司 | Sodium rebeprazole freeze-dried injection |
| WO2010022944A1 (en) * | 2008-09-01 | 2010-03-04 | Stada Arzneimittel Ag | Pharmaceutical pellet |
| US20100172983A1 (en) * | 2001-06-01 | 2010-07-08 | Plachetka John R | Pharmaceutical Compositions for the Coordinated Delivery of Naproxen and Esomeprazole |
| EP2345408A2 (en) * | 2010-01-08 | 2011-07-20 | Dr. Reddy's Laboratories Ltd. | Acid labile drug formulations |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2002098352A2 (en) * | 2001-06-01 | 2002-12-12 | Pozen Inc. | PHARMACEUTICAL COMPOSITIONS FOR THE COORDINATED DELIVERY OF NSAIDs |
| US20100172983A1 (en) * | 2001-06-01 | 2010-07-08 | Plachetka John R | Pharmaceutical Compositions for the Coordinated Delivery of Naproxen and Esomeprazole |
| CN101249078A (en) * | 2008-03-25 | 2008-08-27 | 江苏奥赛康药业有限公司 | Sodium rebeprazole freeze-dried injection |
| WO2010022944A1 (en) * | 2008-09-01 | 2010-03-04 | Stada Arzneimittel Ag | Pharmaceutical pellet |
| EP2345408A2 (en) * | 2010-01-08 | 2011-07-20 | Dr. Reddy's Laboratories Ltd. | Acid labile drug formulations |
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| CN115025087A (en) * | 2022-06-02 | 2022-09-09 | 吉林医药学院 | Preparation method of felodipine-naproxen co-amorphous drug system |
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