CN102247369B - Compound naproxen esomeprazole medicine composition and preparation method thereof - Google Patents
Compound naproxen esomeprazole medicine composition and preparation method thereof Download PDFInfo
- Publication number
- CN102247369B CN102247369B CN 201110237741 CN201110237741A CN102247369B CN 102247369 B CN102247369 B CN 102247369B CN 201110237741 CN201110237741 CN 201110237741 CN 201110237741 A CN201110237741 A CN 201110237741A CN 102247369 B CN102247369 B CN 102247369B
- Authority
- CN
- China
- Prior art keywords
- esomeprazole
- naproxen
- slow
- granules
- granule
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
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, and be particularly useful for the acute attack stage of above-mentioned disease, also can be used for primary dysmenorrhea and medium and small postoperative pain relieving in addition.15 minutes PCs reach peak value after the intravenous injection, and the half-life is 12-14 hour.This medicine is superior to the 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, and taking dose is also big; Not only inconvenient, and needing to be superior to composition fluctuations very big, produce so-called " peak valley " phenomenon, when promptly needing concentration high; Possibly have side effects, even poison, when needing concentration to hang down, may reduce below the treatment concentration; Also just do not produce curative effect of medication, and such oral medicine preparation there is certain damaging action to gastric mucosa after getting into stomach, causes gastrointestinal upset.
Chinese patent CN02112765.4 discloses a kind of production method of naproxen slow releasing capsule.The present invention is employed in and adds 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 after drying, to add Pulvis Talci.
Chinese patent CN02137348.5 relates to a kind of method for preparing 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 scientific 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 (5-methoxyl group-2-[(S)-[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl] sulfinyl]-1H-benzimidazole-1-yl) magnesium salt trihydrate;
Physicochemical property: it is degraded in acid medium rapidly, but it is stable under alkali condition.In pH value 6.8 (relief area) 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 through specific targeting mechanism, for keeping away the specific inhibitor of lipid pump in the cell.Use 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, i.e. catabiosis makes 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 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 PC 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 esomeprazole to be assembled and the needed acidity of activation.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 dose 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.The experimenter, these unit expectations need the condition of NSAID every day to be treatment at least 6 months, if they were at 50 years old, the history in 5 years, geographical sign or duodenal ulcer in the past.These researchs show, 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 (NSAID)/proton pump inhibitor is applicable to the S&S of relief from osteoarthritis (osteoarthritis), rheumatoid arthritis (rheumatoid arthritis) and ankylosing spondylitis (ankylosing spondylitis), in the susceptible patient, can reduce the gastric ulcer risk that causes because of NSAID simultaneously.The osteoarthritis NSAID such as naproxen commonly used treats, and nearly 2,700 ten thousand Americans suffer from this disease.The news that according to what Astrazeneca AB issued that 50% more than the NSAID life-time service person risk with gastrointestinal ulceration was arranged.Chief Medical Technologist Howard doctor Hutchinson of AstraZeneca mentions in a corporate news Press release; " through 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 to treat 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 processed label, and esomeprazole quantitatively is sprayed at the label outside, complicated process of preparation, and domestic realization difficulty is big, and equipment requirements is high, and cost increases.
In order to overcome above-mentioned defective, the upright topic research of special decision a kind of new preparation prescription and preparation technology satisfy domestic clinical application demand, plug a gap.
Summary of the invention
Key in technical field herein and describe paragraph.The object of the 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; Be necessary to work out a kind of suitable prescription and form 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 the half the 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.
The object of the invention provides a kind of compound recipe naproxen esomeprazole pharmaceutical composition, it is characterized in that, processes 1000 prescription and forms as follows:
Immediate-release granules (1) contains:
Esomeprazole magnesium 20-40g (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.
The object of the 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 (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.
The object of the 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 (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 magnesium is mixed and made into immediate-release granules (1) in esomeprazole and adjuvant; As release layer, with the hydrophilic gel matrix material polyethylene glycol 6000 with the naproxen of half recipe quantity process 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 process suitable granularity behind the mix homogeneously is mixed and made into slow-releasing granules (2), as slow release layer; Process double-layer tablet with conventional method: it is characterized in that the preparation process of described immediate-release granules (1) is: with the esomeprazole magnesium of recipe quantity in esomeprazole 100 mesh sieves, then with behind the meglumine and sodium hydroxide mix homogeneously of esomeprazole magnesium in esomeprazole 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 processes 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); The preparation process of described slow-releasing granules (2) is: adopt the spray drying mode to make amorphous forms naproxen, and subsequent use; 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, and the naproxen that adds half recipe quantity then makes its abundant mix homogeneously, is binding agent with 80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30; Add in batches and mix, process 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 method for preparing 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 PA tube and the HDPE bottle.
Below through conceptual design and prescription screening explanation the present invention.
Reach the specific (special) requirements to two kinds of drug releasing rates according to the clinical application characteristics, 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.After oral in vivo also existence need the peak valley phenomenon of concentration, when peak concentration, occur 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, should naproxen 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, in pH value 6.8 (relief area), under 25 ℃ of situation, keeps stability characteristic (quality), 8 hours maintenance stability characteristic (quality)s under 37 ℃ of situation in 19 hours., adjuvant considers basic auxiliary on selecting.
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 with adjuvant sodium hydroxide, meglumine respectively by a certain percentage; 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 the calorstat of 25 ℃ of relative humiditys 92.5% ± 5% (KNO3 saturated solution) placed 10 days, investigate appearance character and related substance, the result sees the following form:
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 basis, basically reasonably write out a prescription for several kinds below the design, so that launch screening and optimization to the relevant research of the supplementary material compatibility.
Esomeprazole immediate-release granules (1) prescription screening
Preparation technology:
Prescription 1: with the esomeprazole magnesium of recipe quantity in esomeprazole 100 mesh sieves, then with esomeprazole magnesium in esomeprazole and the abundant mixing of recipe quantity lactose, be binding agent with 80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30; Add in batches and mix, process 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: with the esomeprazole magnesium of recipe quantity in esomeprazole 100 mesh sieves, with behind the meglumine and sodium hydroxide mix homogeneously of esomeprazole magnesium in esomeprazole and recipe quantity, add the abundant mixing of lactose more then; 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent, adds in batches and mixes, and processes to be fit to the soft material of granulating; 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 mensuration result
Stripping curve is measured the result
Can know by above result of the test: 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, and respectively to investigate index all up to specification for the prescription 2 of trial-production under the basic auxiliary environment, 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, is binding agent with 80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30; Add in batches and mix, process 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 mensuration result
Release profiles is measured the result
Can be known by above result of the test: prescription 3-writes out a prescription under the situation of 5 angle of reposes, character, hardness, the equal no significant difference of friability, the releasing trend of prescription 5 obviously be superior to writing out a prescription 3 with 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)
With the esomeprazole magnesium of recipe quantity in esomeprazole 100 mesh sieves, with behind the meglumine and sodium hydroxide mix homogeneously of esomeprazole magnesium in esomeprazole and recipe quantity, add the abundant mixing of lactose more then; 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent, adds in batches and mixes, and processes 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, is binding agent with 80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30; Add in batches and mix, process 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, the calorstat held of 4500LX ± 500 LX illumination, 60 ℃ ± 2 ℃, 25 ℃ relative humiditys 75% ± 5% (NaCl saturated solution) 10 days, detects respectively in sampling in 0,5,10 day:
Above result of the test can be known; Naproxen esomeprazole sheet is placed 5 days sampling and measuring at the calorstat of 25 ℃ of relative humiditys 75% ± 5% (NaCl saturated solution), and 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; The accelerated test condition held 6 months of relative humidity 75% ± 5% and long term test condition were placed 6 months, and the result shows, the more stable accords with production requirement of quality.
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 done further explain, but should understand 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 (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 the esomeprazole magnesium of recipe quantity in esomeprazole 100 mesh sieves, with behind the meglumine and sodium hydroxide mix homogeneously of esomeprazole magnesium in esomeprazole and recipe quantity, add the abundant mixing of lactose more then; 80% alcoholic solution with 6% 30 POVIDONE K 30 BP/USP 30 is a binding agent, adds in batches and mixes, and processes 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 forms naproxen, and subsequent use; 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, and the naproxen that adds half recipe quantity then makes its abundant mix homogeneously, is binding agent with 80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30; Add in batches and mix; Process 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 gets.
Embodiment 2
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Immediate-release granules (1) contains:
Esomeprazole magnesium 20g (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 (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 (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 (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. adopt the spray drying mode to make amorphous forms naproxen, subsequent use;
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);
With the esomeprazole magnesium of recipe quantity in esomeprazole 100 mesh sieves, then with behind the meglumine and sodium hydroxide mix homogeneously of esomeprazole magnesium in esomeprazole 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 processes 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, is binding agent with 80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30; Add in batches and mix; Process 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 gets.
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 (4)
1. compound recipe naproxen esomeprazole pharmaceutical composition; It is characterized in that; 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, immediate-release granules (1) and slow-releasing granules (2) are made up of the main ingredient of following weight proportion in the compound recipe naproxen esomeprazole pharmaceutical composition:
1000 of compound recipe naproxen esomeprazole sheet unit prescriptions, wherein:
Immediate-release granules (1) contains:
Esomeprazole magnesium is in esomeprazole 20-40g
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.
2. 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 is in esomeprazole 20g
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.
3. 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 is in esomeprazole 20g
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.
4. the said compound recipe naproxen of claim 1-3 esomeprazole preparation of drug combination method; Be that esomeprazole magnesium is mixed and made into immediate-release granules (1) in esomeprazole and adjuvant; As release layer, with the hydrophilic gel matrix material polyethylene glycol 6000 with the naproxen of half recipe quantity process 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 process suitable granularity behind the mix homogeneously is mixed and made into slow-releasing granules (2), as slow release layer; Process double-layer tablet with conventional method: it is characterized in that the preparation process of described immediate-release granules (1) is: with the esomeprazole magnesium of recipe quantity in esomeprazole 100 mesh sieves, then with behind the meglumine and sodium hydroxide mix homogeneously of esomeprazole magnesium in esomeprazole 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 processes 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); The preparation process of described slow-releasing granules (2) is: adopt the spray drying mode to make amorphous forms naproxen, and subsequent use; 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, is binding agent with 80% alcoholic solution of 6% 30 POVIDONE K 30 BP/USP 30, adds in batches and mixes; Process 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 45-55 ℃; Solid dispersion granule and this granule mix homogeneously are made granule (2), adopt conventional method for preparing to be pressed into double-layer tablet immediate-release granules (1) and slow-releasing granules (2).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110237741 CN102247369B (en) | 2011-08-18 | 2011-08-18 | Compound naproxen esomeprazole medicine composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110237741 CN102247369B (en) | 2011-08-18 | 2011-08-18 | Compound naproxen esomeprazole medicine composition and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102247369A CN102247369A (en) | 2011-11-23 |
| CN102247369B true CN102247369B (en) | 2012-11-21 |
Family
ID=44975176
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110237741 Active CN102247369B (en) | 2011-08-18 | 2011-08-18 | Compound naproxen esomeprazole medicine composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102247369B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115025087A (en) * | 2022-06-02 | 2022-09-09 | 吉林医药学院 | Preparation method of felodipine-naproxen co-amorphous drug system |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002098352A2 (en) * | 2001-06-01 | 2002-12-12 | Pozen Inc. | PHARMACEUTICAL COMPOSITIONS FOR THE COORDINATED DELIVERY OF NSAIDs |
| CN101249078A (en) * | 2008-03-25 | 2008-08-27 | 江苏奥赛康药业有限公司 | Sodium rebeprazole freeze-dried injection |
| EP2345408A2 (en) * | 2010-01-08 | 2011-07-20 | Dr. Reddy's Laboratories Ltd. | Acid labile drug formulations |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100172983A1 (en) * | 2001-06-01 | 2010-07-08 | Plachetka John R | Pharmaceutical Compositions for the Coordinated Delivery of Naproxen and Esomeprazole |
| DE102008045339A1 (en) * | 2008-09-01 | 2010-03-04 | Stada Arzneimittel Ag | Pharmaceutical pellet |
-
2011
- 2011-08-18 CN CN 201110237741 patent/CN102247369B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002098352A2 (en) * | 2001-06-01 | 2002-12-12 | Pozen Inc. | PHARMACEUTICAL COMPOSITIONS FOR THE COORDINATED DELIVERY OF NSAIDs |
| CN101249078A (en) * | 2008-03-25 | 2008-08-27 | 江苏奥赛康药业有限公司 | Sodium rebeprazole freeze-dried injection |
| EP2345408A2 (en) * | 2010-01-08 | 2011-07-20 | Dr. Reddy's Laboratories Ltd. | Acid labile drug formulations |
Non-Patent Citations (2)
| Title |
|---|
| Sohita Dhillon, et al..naproxen/esomeprazole fixed-dose combination: for the treatment of arthritic symptoms and to reduce the risk of gastric ulcers.《Drugs Aging》.2011,第28卷(第3期),237-248. * |
| 药讯快递.Vimovo(PN400)申请用于关节炎.《临床合理用药》.2009,第2卷(第13期),11. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102247369A (en) | 2011-11-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2625676A1 (en) | Stabilized extended release pharmaceutical compositions comprising a beta-adrenoreceptor antagonist | |
| UA52679C2 (en) | Pharmaceutical multiple unit formulation and method for its preparation | |
| KR101156054B1 (en) | A stable and control-released pharmaceutical composition comprising eperisone | |
| CN101069675A (en) | A method of alleviating signs and symptons of spasticity | |
| WO2000050014A2 (en) | Phenytoin sodium pharmaceutical compositions | |
| KR20030036877A (en) | Sustained release pharmaceutical compositions containing metformin and method of its production | |
| CN103239725A (en) | Compound preparation for treating cardiovascular and cerebrovascular diseases | |
| CN102247369B (en) | Compound naproxen esomeprazole medicine composition and preparation method thereof | |
| CN107412198A (en) | Duloxetine hydrochloride enteric slow release granule and preparation method thereof | |
| CN105431140B (en) | Compound formulation containing slow release of metformin and quick-release HMG-CoA reductase inhibitor | |
| CN102294031B (en) | Pharmaceutical formulation comprising proton pump inhibitor, NSAID and antacids | |
| TWI608849B (en) | High drug load pharmaceutical compositions with controllable release rate and production methods thereof | |
| WO2010080977A2 (en) | Oral sustained release antidepressant formulation | |
| CN101342177B (en) | Lornoxicam double-layer sustained release tablets | |
| CN103282051A (en) | Orally disintegrating tablet | |
| CN102697749A (en) | Preparation method of benazepril hydrochloride tablets | |
| KR20070024521A (en) | The combination for treating hyperlipemia | |
| CN102349909A (en) | Pharmaceutical composition for lowering blood lipid | |
| US8512746B2 (en) | Extended release pharmaceutical compositions of levetiracetam | |
| CN202288921U (en) | Compound naproxen esomeprazole tablet | |
| CN100563636C (en) | Acemetacin sustained-release preparation and preparation method | |
| CN114224878B (en) | Compound medicine for treating Parkinson's disease | |
| CN100363001C (en) | Moxifloxacin capsule and its preparation method | |
| Subburayalu et al. | Formulation and stabilization of aspirin mini-tablets with the aid of weak acid and moisture protective coating | |
| US8865210B2 (en) | Stable dosage formulations of imidazolylalkyl-pyridines |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: BEIJING HONGLIN PHARMACY CO., LTD. Free format text: FORMER OWNER: TIANJIN SONGRUI MEDICAL TECHNOLOGY CO.,LTD. Effective date: 20141010 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 300250 HEDONG, TIANJIN TO: 101407 HUAIROU, BEIJING |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20141010 Address after: 101407 Beijing Yanqi Yanqi Industrial Development Zone, Huairou District, two East Road No. 28 Patentee after: Beijing Honglin Pharmaceutical Co., Ltd. Address before: 300250, Taixing building, Taixing Road, Hedong District, Tianjin, building 14, gate 1, 102 Patentee before: Tianjin Songrui Medical Technology Co.,Ltd. |