CN102499908A - Alvimopan solid preparation and preparation method thereof - Google Patents

Abstract

The invention provides an alvimopan solid preparation with high bioavailability and a preparation method thereof. The preparation comprises 0.5-1 parts of alvimopan, 10-100 parts of chitosan, 1-10 parts of 5-10% glutaraldehyde aqueous solutions, 20-300 parts of medicinal solvents, and 2-200 parts of pharmaceutic adjuvants. The preparation method comprises the following steps: firstly dissolving chitosan in the medicinal solvent, adding alvimopan and dissolving, slowly adding the 5-10% glutaraldehyde aqueous solution, uniformly stirring, performing spray drying to obtain alvimopan chitosan microspheres, finally mixing with the pharmaceutic adjuvant, directly compressing tablets or filling in capsules. The alvimopan solid preparation prepared by the invention can significantly improve the bioavailability, and beagle dog animal experiment shows that the bioavailability increases from 4.06% to 9.15%. The solid preparation is more suitable for large-scale industrial production.

Description

A kind of alvimopan solid preparation and preparation method thereof

Technical field

The invention belongs to technical field of medicine, relate to and be used to treat periphery property bowel dysfunction that opioid drug causes and alvimopan solid preparation of postoperative ileus and preparation method thereof.

Background technology

Intestinal contents can not normally move or be called intestinal obstruction (ileus) when obstacle takes place.Intestinal obstruction is a kind of disease that lacks bowel movement property that is characterized as.Usually, intestinal obstruction comes across whole intestinal (for example large intestine and small intestinal), but also relates to one or more sections of intestinal sometimes, and intestinal obstruction not only can cause intestinal tube dissection itself and physiological change, and can cause the general physiologic derangement.The state of an illness is complicated and changeable clinically, postoperative ileus particularly, and it is a kind of common short-term intestinal injury disease that all kinds of abdominal paries or other surgical operation postoperatives occur, its symptom can sb.'s illness took a turn for the worse because of multiple factor causes.Postoperative ileus is not only and is caused the one of the main reasons that patient's postoperative rehabilitation process is slowed down, the hospital stays prolongs, the extra charge expenditure increases, and also is one of potential cause that causes the medical resource burden.Although in the last few years, along with the improvement with Therapeutic Method that improves constantly, treat ileac effect and be greatly improved its pathology, physiology understanding, be in a bad way mortality rate like strangulated intestinal obstruction still about 10%.At present, targetedly real both at home and abroad efficacious therapy medicine has only alvimopan, and therefore, its market prospect is very wide.

Alvimopan (Alvimopan) is periphery selectivity μ-opioid receptor antagonist, is used to treat periphery property bowel dysfunction and the postoperative ileus that opioid drug causes clinically.Its chemical name: [[(2S)-2-[[(3R, 4R)-4-(3-hydroxy phenyl)-3,4-lupetidine-1-yl] methyl]-3-phenyl propiono] amino] acetic acid, general alvimopan by name (Alvimopan).Its structural formula:

Because the oral absorption of alvimopan seldom, and exist very strong first pass effect of hepar, cause intravital plasma drug level variation big; According to bibliographical information; The beagle dog bioavailability result of the test of alvimopan is merely 0.03%, and according to another the foreign patent bibliographical information, alvimopan has capsule, oral liquid and three kinds of dosage forms of freeze-dried powder; But the bioavailability of its capsule and oral liquid is still lower, the highlyest is about 6%.The alvimopan capsule of external listing is a dosage form commonly used clinically, and according to foreign patent EP0984004A2 report, its capsular prescription and preparation technology are following:

Preparation technology: all solids composition is sieved, Polyethylene Glycol is melted and the maintenance molten condition.Said medicine is mixed above-mentioned fusion carrier.With suitable oily paste filling equipment with the described fused homogeneous suspension liquid hard gelatin capsule of packing into.It is thus clear that, in the capsular preparation process of alvimopan, there is following difficult point:

1) consider technically: the alvimopan crude drug does not only dissolve in liquid polyethylene glycol (temperature is 65 ℃), and the meeting sedimentation, and therefore for guaranteeing that uniformity of dosage units is qualified, sedimentation must not take place in Polyethylene Glycol raw material, is a homogeneous suspension liquid.On the one hand raw material needs enough carefully, generally is controlled at below the 50um through particle diameter behind the micronization, if particle diameter greatly then sedimentation is fast, thereby influences the homogeneity of its preparation, further influences bioavailability and curative effect; On the other hand, in pouring process, need to stir synchronously.

2) consider on the slave unit: the capsular preparation of alvimopan need be with the fused homogeneous suspension liquid hard gelatin capsule of packing into, and this just needs special filling apparatus (liquid capsule filling machine), and whole production line need heat and attemperator (temperature is 65 ℃); To guarantee the liquid condition of Polyethylene Glycol, be fit to fill, but the present domestic manufacturer that does not have this equipment; Though this equipment is abroad arranged; But cost an arm and a leg, this has not only increased the preparation difficulty, has also increased the preparation cost simultaneously.

Summary of the invention

The shortcoming that the objective of the invention is to overcome prior art provides alvimopan solid preparation of a kind of high bioavailability and preparation method thereof with not enough.For realizing this purpose, the present invention provides following technical scheme:

A kind of alvimopan solid preparation, it is characterized in that it is made up of the alvimopan granule and the pharmaceutic adjuvant of enclose: described enclose alvimopan granule is meant chitosan, alvimopan is dissolved in medicinal solvent; Slowly add the 5-10% glutaraldehyde water solution, then through direct spray drying be sprayed on lactose or the microcrystalline Cellulose bead on process.Medicinal solvent wherein is dilute hydrochloric acid or spirit of vinegar.

The preferred alvimopan solid preparation of the present invention, it is made up of the raw material of following weight:

Medicinal solvent wherein is dilute hydrochloric acid or spirit of vinegar; Pharmaceutic adjuvant is lactose, spray drying mannitol, microcrystalline Cellulose, pre-paying starch (starch1500), low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, Polyethylene Glycol, polyvidone, magnesium stearate, castor oil hydrogenated or silicon dioxide.

Solid preparation of the present invention is capsule or tablet.

Alvimopan of the present invention refers to 0-2 crystalline hydrate.

The viscosity-average molecular weight of chitosan according to the invention is 1-10 ten thousand, and its consumption is 10-100 part.Preferred parts by weight are 20-60 part.

The parts by weight of 5-10% glutaraldehyde water solution according to the invention are 1-10 part, preferred 3-6 part.

The parts by weight of medicinal solvent according to the invention are 20-300 part, preferred 50-300 part, and its concentration is 0.05-1mol/L, preferred 0.1-0.3mol/L.

As preferred alvimopan solid preparation of the present invention, it is made up of following materials based on weight:

As another preferred alvimopan solid preparation of the present invention, it is made up of the alvimopan granule and the pharmaceutic adjuvant of enclose: described enclose alvimopan granule is meant chitosan, alvimopan is dissolved in medicinal solvent; Slowly add the 5-10% glutaraldehyde water solution, then through direct spray drying be sprayed on lactose or the microcrystalline Cellulose bead on process.Wherein said pharmaceutic adjuvant is lactose, polyethylene glycol 6000, mannitol, microcrystalline Cellulose, pre-paying starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate or castor oil hydrogenated; Its raw materials in part by weight is formed as follows:

The present invention further discloses the method for preparing of alvimopan solid preparation, it is to be undertaken by following step:

(1) medicinal solvent of selection 20-300 part adds the chitosan stirring and dissolving;

(2) add the dissolving of 0.5-1 part alvimopan, obtain chitosan alvimopan solution;

(3) it is an amount of slowly to add the 5-10% glutaraldehyde water solution, stirs;

(4) obtain chitosan alvimopan microsphere with solution is spray-dried, or be sprayed on the lactose microsphere that obtains the chitosan alvimopan on the lactose bead;

(5) comprising behind alvimopan microsphere and the pharmaceutic adjuvant mix homogeneously tabletting or incapsulate gained.

The technical problem that the present invention will solve is: alvimopan not only contains amino but also contain hydroxy-acid group; The character that similar polypeptide is arranged; Belong to highly dissoluble hypotonicity medicine, its strongly hydrophilic group causes increasing with the affinity of cell in vivo, easily by macrophage phagocytic; And then be difficult for being absorbed, cause bioavailability to reduce.The present invention adopts the chitosan of biodegradable natural origin as raw material, and the alvimopan of indissoluble is dissolved solubilising and parcel, makes its extension body internal recycle, reduces reticuloendothelial cell and engulfs, thereby improve bioavailability.

High spot reviews of the present invention following key issue:

1) choice of Solvent: alvimopan is insoluble in water; But certain dissolubility is arranged in diluted acid or alkaline solution; Chitosan is the meta-alkalescence material; Also in diluted acid, dissolve, therefore select dilute hydrochloric acid (concentration is about 0.1-0.3mol/L) or acetic acid (concentration is about 0.1-0.3mol/L) the best for use, addition selection optimal proportion is about 50-250 times of raw material alvimopan;

2) selection of chitosan: select the chitosan of biodegradable natural origin for use, its viscosity-average molecular weight is 10000-100000, and the 20-60 that addition is about alvimopan is doubly best;

3) method for preparing of alvimopan chitosan: spray drying method, film forming coating method;

4) selection of pharmaceutic adjuvant: the inventor has investigated adjuvants such as lactose, mannitol, calcium hydrogen phosphate, microcrystalline Cellulose, pre-paying starch, magnesium stearate, silicon dioxide, and the result shows that above-mentioned adjuvant and the alvimopan compatibility are good.

The alvimopan capsule (embodiment 3) of the present invention's preparation, for the oral bioavailability of beagle dog, the alvimopan capsule for preparing with listing article method compares, and its method and result are following:

Two of one group of oral 12mg/ capsules of two groups of Beagle dogs, one group of drug administration by injection; Drinking water is freely got in administration after 4 hours; Every dog is in preceding, 5,10,15,30 after the taking medicine of taking medicine, 45min and sampling in 1,2,3,4,6,9,12 hour; Adopt instrument TSQ QuantumDiscoverMAX type liquid chromatography-mass spectrography-GC-MS, its blood drug level of internal mark method determination.According to the area (AUC under blood drug level-time graph _0-12h) calculating the absolute bioavailability (F%) of oral alvimopan, the result sees the following form:

Annotate: iv intravenous injection ss: listing article zz: own product

Can be known that by last table result its absolute bioavailability of capsule of listing article method preparation is 4.06 ± 2.83, its absolute bioavailability of capsule of the present invention's preparation is 9.15 ± 4.8; The capsule of kind of method preparation has significant difference on bioavailability through statistical analysis: P＜0.05, two.

The good effect that alvimopan solid preparation provided by the invention is compared with prior art had is:

(1) the alvimopan solid preparation of the present invention's preparation can make bioavailability obviously improve, and the zoopery of beagle dog shows: bioavailability is increased to 9.15% from 4.06%.

(2), using dosage is significantly reduced for same curative effect prerequisite; Conservation can reduce the side effect that possibly bring because of the dosage height on the other hand on the one hand.

(3) compare when the liquid capsule that has abroad gone on the market is produced and need the liquid capsule filling machine, and domesticly do not have a corresponding production equipment, therefore, the present invention more is prone to realize on producing.

The specific embodiment:

For simple and purpose clearly, the omission that hereinafter is appropriate the description of known technology, in order to avoid those unnecessary details influences are to the description of present technique scheme.Below in conjunction with instance the present invention is done further explanation.Wherein used supplementary material all has commercially available.

Embodiment 1

Prescription: alvimopan (anhydride) 6g

Chitosan (viscosity-average molecular weight 10,000) 120g

5% glutaraldehyde water solution 18ml

Microcrystalline Cellulose 180g

Hydroxypropyl methylcellulose 30g

Carboxymethyl starch sodium 12g

Magnesium stearate 2g;

Preparation technology:

The chitosan of 120g is dissolved in 480ml 0.1mol/L hydrochloric acid, stirs and dissolve clearly, add alvimopan (anhydride) 6g, stir, slowly add 5% glutaraldehyde water solution 18ml again, stir 10min; It is spray-dried that (90 ± 2 ℃ of EATs, outlet temperature are about 50 ± 2 ℃; Hydrojet flow velocity 5ml/min, nozzle exit pressure 0.4Mpa), obtain the bead of shape homogeneous.Add other adjuvants, the mixing direct compression.

Embodiment 2

Prescription: alvimopan (monohydrate) 6g

Chitosan (viscosity-average molecular weight 60,000) 240g

10% glutaraldehyde water solution 36ml

Microcrystalline Cellulose 180g

Polyethylene glycol 6000 20g

Pregelatinized Starch 30g

Cross-linking sodium carboxymethyl cellulose 12g

Magnesium stearate 2g;

Preparation technology:

The chitosan of 240g is dissolved in the 0.3mol/L acetic acid of 960ml, stirs and dissolve clearly, add alvimopan (1 hydrate) 6g, stir, slowly add 10% glutaraldehyde water solution 36ml again, stir 10min; It is spray-dried that (90 ± 2 ℃ of EATs, outlet temperature are about 50 ± 2 ℃; Hydrojet flow velocity 5ml/min, nozzle exit pressure 0.4Mpa), obtain the bead of shape homogeneous.Add other adjuvants, the mixing direct compression.

Embodiment 3

Prescription: alvimopan (dihydrate) 6g

Chitosan (viscosity-average molecular weight 60,000) 360g

Magnesium stearate 4g;

Technology: the chitosan of 360g is dissolved in the 0.1mol/L acetic acid of 1500ml, and the same method operation obtains the bead of shape homogeneous.Add magnesium stearate, encapsulated.

Embodiment 4

Prescription: alvimopan (dihydrate) 6g

Chitosan (viscosity-average molecular weight 100,000) 120g

5% glutaraldehyde water solution 24ml

Lactose microsphere 287g

Microcrystalline Cellulose 74g

Polyvidone k30 12g

Low-substituted hydroxypropyl cellulose 12.5g

Silica 1 .5g

Magnesium stearate 3g;

Preparation technology:

The chitosan of 120g is dissolved in the 0.1mol/L hydrochloric acid of 500ml, stirs and dissolve clearly, add alvimopan 6g, stir, slowly add 5% glutaraldehyde water solution 24ml again, stir 10min; (80 ± 2 ℃ of EATs, outlet temperature are about 45 ± 2 ℃ to the lactose microsphere through the atomizing coating; Flow velocity 6ml/min, nozzle exit pressure 0.4Mpa), obtain the lactose microsphere of alvimopan chitosan.Add other adjuvants, the mixing direct compression.

Embodiment 5

Prescription: alvimopan (dihydrate) 6g

Chitosan (viscosity-average molecular weight 100,000) 120g

Lactose microsphere 287g

Castor oil hydrogenated 3g;

Technology: the same method obtains the lactose microsphere of alvimopan chitosan.Add castor oil hydrogenated, encapsulated.

Claims (7)

1. alvimopan solid preparation, it is characterized in that it is made up of the alvimopan granule and the pharmaceutic adjuvant of enclose: described enclose alvimopan granule is meant chitosan, alvimopan is dissolved in medicinal solvent; Slowly add the 5-10% glutaraldehyde water solution, then through direct spray drying or be sprayed on the bead and process; Medicinal solvent wherein is dilute hydrochloric acid or spirit of vinegar.

2. the described alvimopan solid preparation of claim 1, it is made up of the raw material of following weight:

Medicinal solvent wherein is dilute hydrochloric acid or spirit of vinegar; Pharmaceutic adjuvant is lactose, mannitol, microcrystalline Cellulose, pre-paying starch, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, Polyethylene Glycol, polyvidone, magnesium stearate, castor oil hydrogenated or silicon dioxide.

3. claim 1 or 2 described solid preparations, solid preparation wherein is capsule or tablet.

4. claim 1 or 2 described solid preparations, alvimopan wherein refers to 0-2 crystalline hydrate.

5. claim 1 or 2 described solid preparations, wherein the viscosity-average molecular weight of chitosan is 1-10 ten thousand.

6. claim 1 or 2 described solid preparations, wherein the parts by weight of medicinal solvent are 50-300 part, its concentration is 0.05-1mol/L.

7. the method for preparing of the said alvimopan solid preparation of claim 2 is characterized in that being undertaken by following step:

(1) medicinal solvent of selection 20-300 part adds the chitosan stirring and dissolving;

(2) add the dissolving of 0.5-1 part alvimopan, obtain chitosan alvimopan solution;

(3) it is an amount of slowly to add the 5-10% glutaraldehyde water solution, stirs, and obtains solution;

(4) obtain chitosan alvimopan microsphere with solution is spray-dried, or be sprayed on the lactose microsphere that obtains the chitosan alvimopan on the lactose bead;

(5) with tabletting behind gained alvimopan microsphere and the pharmaceutic adjuvant mix homogeneously or incapsulate.