CN1968680A - Compositions and dosage forms for enhanced absorption of gabapentin and pregabalin - Google Patents

Abstract

A complex comprised of metformin and a transport moiety, such as a alkyl sulfate, is described. The complex has an enhanced absorption in the gastrointestinal tract, particularly the lower gastrointestinal tract. The complex, and compositions and dosage forms prepared using the complex, provide for absorption by the body of the drug through a period of ten to twenty-four hours, thus enabling a once-daily dosage form for metformin.

Description

Promote the compositions and the dosage form of the absorption of gabapentin and pregabalin

Background of invention

The present invention relates to be used to discharge the compositions and the dosage form of gabapentin or pregabalin.More particularly, the present invention relates to the complex of gabapentin or pregabalin and transhipment part, wherein this complex promotes medicine in gastrointestinal tract and the more especially absorption in lower gastrointestinal tract.

Background of invention

About the pathogenetic understanding of science of neuropathic pain in the past 10 years developed, the basic research of neuropathic pain animal model and people's clinical trial have disclosed because damage or disease make nervous system generation Pathophysiology and biochemistry change (Backonja, M.M., Clin.J.Pain 16(2): S67-72 (2000)).Neuropathic pain is a chronic disease, appears at cancer patient, stroke victim, old people, diabetics (as the diabetic neuropathy of pain), herpes zoster (herpes zoster) patient (as postherpetic neuralgia) and patients with neurodegenerative (for example amyotrophic lateral sclerosis (ALS)) usually.The Clinical symptoms of neuropathic pain comprises burn feeling, spontaneous pain, shooting pain and brings out pain (evoked pains).Different pathophysiological mechanisms causes the specificity sensory symptoms, for example dynamic mechanically allodynia and crymodynia allergy.

The Therapeutic Method of neuropathic pain comprises with conventional analgesics NSAID (non-steroidal anti-inflammatory drug), analgesic, papaveretum or tricyclics (Max, M.B., Ann.Neurol., 35 (Suppl): S50-S53 (1994) for example; Raja, S.N. etc., the neurological, 59: 1015 (2002); Galer, B.S. etc., Pain, 80: 533 (1999)).So because abundant alleviating pain or have insupportable side effect and do not accepted of these medicines and other therapy by many patients.

Proved the anticonvulsant gabapentin treatment neuropathic pain diabetic neuropathy and the postherpetic neuralgia of pain (and particularly treat) have obvious analgesic activity (Wheeler, G., Curr.Opin.Invest, Drugs, 3(3): 470 (2002)).Gabapentin still control some type epilepsy especially the active drug of the epilepsy that causes of epilepsy (Johannessen, S.I. etc., Ther.Drug Monitoring (drug monitoring), 25: 347 (2003)).Similarly, pregabalin shown effective treatment belt shape postherpetic neuralgia and pain diabetic neuropathy (Dworkin, R.H. etc., the neurological, 60: 1274 (2003)).

Gabapentin is absorbed into blood flow (Johannessen, supra is at 350 pages) by L-amino acid transport system from proximal small bowel.Bioavailability of medicament is dose-dependent, obviously be because L-amino acid transport system saturated, limited medicine absorbtivity (Stewart, B.H. etc., Pharm.Res., 10: 276 (1993)).For example, serum gabapentin concentration increases to the dosage linearity and is up to about 1800mg/d, then higher but be lower than and continue under the dosage of expection to increase, may be because the mechanism that absorbs from upper gastrointestinal becomes saturated (Stewart, the same (supra.)).

The amino movement system of L-that be responsible for to absorb gabapentin mainly be present in the epithelial cell of small intestinal (Kanai, Y.J. etc., J.Toxicol.Sci., 28(1): 1 (2003)), thus the absorption of limit drug.Pregabalin also shows by the amino movement system of L-and other amino acid transport system absorption ((Dworkin, supra, 1282 pages).

The difference of upper gastrointestinal and lower gastrointestinal tract cell characteristic also causes the deficiency of lower gastrointestinal tract molecule absorption.Fig. 1 illustrates the 2 kind conventional route of transhipment chemical compound by the gastrointestinal tract epithelium.The individual epithelial cell of being represented by 10a, 10b, 10c forms barrier cell along small intestinal and large intestine.Individual cells is by aquaporin or closely connection (for example 12a, 12b) separation.Transhipment by epithelium both can also can all can through parietal cell passage or both through striding cell passage.The cell passage (as the arrow 14 of Fig. 1) of striding of transhipment is meant that chemical compound moves by passive diffusion or carrier mediated transhipment and strides across epithelial cell wall and cyton.The parietal cell passage of transhipment is meant that molecule moves through each intercellular tight connection, and is as shown in arrow 16.Parietal cell passage specificity is lower but total capacity is much bigger, in part because it is present in whole gastrointestinal tract.But, closely connect along gastrointestinal tract distribution difference, close-connected effectively " compactness " is increase trend from near-end to far-end.Therefore, upper gastrointestinal duodenum is than upper gastrointestinal ileum more " leakiness ", ileum than the colon of lower gastrointestinal tract more " leakiness " (Knauf, H. etc., Klin.Wochenschr., 60(19): 1191-1200 (1982)).

Because medicine is from about 4 to 6 hours in the upper gastrointestinal common time of staying, so only 4 to 6 hour time period absorbed by body the medicine of colon absorption difference after oral absorption.What medically wish usually is that the medicine whole day of giving that appears in patient's blood flow keeps relative constant density.For reaching this point, the patient will need every day and take medicine 3 to 4 times during the conventional medicine preparation that absorbs with the minimum colon of performance.It is not a therapeutic regimen above this patient's of being not easy to the practical experience.Therefore, need to obtain the medicine of the long-term absorption of such whole day and 1 administration every day.

For the treatment of constant dosage is provided, the conventional medicine development has proposed various control and has discharged drug system.Such system plays a role by an elongated segment after administration discharges them in the time medicine payload.But the conventionally form that absorbs these Controlled Release System under the minimum situation at the medicine colon is invalid.Because medicine only absorbs and because medicine has only 4 to 6 hours in the upper gastrointestinal time of staying in upper gastrointestinal, do not mean and stop through upper gastrointestinal that body will continue absorption sustained release medicine after 4 to 6 hours so the sustained release dosage form dosage form in upper gastrointestinal that proposes still can discharge the fact of its payload after the time of staying.On the contrary, dosage form has entered the medicine that the sustained release dosage form discharges behind the lower gastrointestinal tract and has not absorbed usually, but discharges from body with other material of lower gastrointestinal tract.

If gabapentin appears in patient's blood flow with the medicine effective concentration whole day, the purposes of this medicine Taking Control of Epilepsy outbreak or neuropathic pain will greatly be improved so.For reaching this point when using conventional gabapentin formulation, the patient will need to take in gabapentin dosage every day 3 to 4 times.This patient's of being not easy to practical experience shows that it is not a therapeutic regimen.In addition, 1 time gabapentin therapy will provide and surpass advantage easily real every day.The constant relatively dosage of gabapentin provides many other advantages in patient's blood flow.Therefore, need to obtain the gabapentin of long-term 1 administration every day that absorbs of whole day.

Summary of the invention

Therefore, the present invention includes material, gabapentin or pregabalin that contains gabapentin or pregabalin and transhipment part and the complex that transhipment partly forms on the one hand.

In one embodiment, transhipment part is the alkyl sulfate with 6-12 carbon atom.Preferred alkyl sulfate is a lauryl sulfate.

On the other hand, the present invention includes the complex partly be made up of gabapentin or pregabalin and transhipment and the compositions of pharmaceutically acceptable carrier, wherein said composition infra gastrointestinal is absorbed as gabapentin or pregabalin at least 5 times.

On the other hand, the present invention includes an embodiment of the dosage form that contains above-described compositions or above-described material.

In one embodiment, dosage form is an osmotic dosage form.In one embodiment, exemplary dosage forms has (i) promoting layer; The medicine layer that (ii) contains gabapentin-transhipment part complex or pregabalin-transhipment part complex; (iii) center on the semi-permeable wall of promoting layer and medicine layer; (iv) outlet.Another kind of exemplary dosage forms has (i) semi-permeable wall around infiltration preparation gabapentin-transhipment part complex or pregabalin-transhipment part complex, penetrating agent and osmopolymer; (ii) outlet.

In one embodiment, dosage form provides the total daily dose between the 200-3600mg.

On the other hand, the invention provides the improvement dosage form that contains gabapentin or pregabalin.This improvement comprises and contains gabapentin or pregabalin and the transhipment part dosage form with the associating complex of tight ion pair key.

On the other hand, the present invention includes the method that gabapentin or pregabalin is delivered medicine to (comprising above-described material) patient who needs them.

In one embodiment, this material is an oral administration.

On the other hand, the present invention includes the method for the complex of preparation gabapentin or pregabalin and transhipment part, comprise gabapentin or pregabalin are provided; The transhipment part is provided; Gabapentin or pregabalin and transhipment part in being lower than the solvent of water, dielectric constant is combined; Thereby it is described in conjunction with the complex that forms gabapentin or pregabalin and transhipment part.

In one embodiment, in conjunction with comprising that (i) makes gabapentin or pregabalin combine in aqueous solvent with the transhipment part, the solvent that (ii) dielectric constant is lower than water adds in this aqueous solvent and (iii) reclaim complex from this solvent.

In another embodiment, be lower than in dielectric constant at least two/one the solvent of water and contact in conjunction with being included in dielectric constant.Exemplary solvent comprises methanol, ethanol, acetone, benzene, dichloromethane and carbon tetrachloride.

On the other hand, the present invention includes the method for improving gabapentin or pregabalin gastrointestinal absorption, comprise the complex that contains gabapentin or pregabalin and transhipment part is provided, the feature of this complex is tight ion pair key; And complex delivered medicine to the patient.

In one embodiment, the absorption of improvement comprises the absorption that improves lower gastrointestinal tract.

In another embodiment, the absorption of improvement comprises the upper gastrointestinal absorption of improvement.

These aspects, the same with other aspects, features and advantages of the present invention, from the detailed open and appended claim of the present invention hereinafter, will become clearer.

The accompanying drawing summary

The following drawings is not to draw in proportion, and to put forward be for difference of the present invention is described

Embodiment.

Fig. 1 is the sketch of gastrointestinal tract epithelial cell, illustrates that transport molecule strides cell passage and parietal cell passage by epithelium;

Fig. 2 A represents the chemical constitution of gabapentin;

Fig. 2 B represents the chemical constitution of pregabalin;

Fig. 3 A represents to prepare the general synthetic reaction flow process of gabapentin-transhipment part or pregabalin-transhipment part complex;

Fig. 3 B represents to prepare the general synthetic reaction flow process of gabapentin-transhipment part or pregabalin-transhipment part complex, and wherein this transhipment part comprises sulfate groups;

Fig. 3 C represents to prepare the synthetic reaction flow process of gabapentin-alkylsurfuric acid salt complex;

Fig. 3 D represents to prepare the synthetic reaction flow process of pregabalin-alkylsurfuric acid salt complex;

Fig. 4 A-4D is the FTIR scanning of the physical mixture (loose ion pair) (Fig. 4 C) and the gabapentin-lauryl sulfate salt complex (Fig. 4 D) of gabapentin (Fig. 4 A), sodium lauryl sulfate (Fig. 4 B), gabapentin and sodium lauryl sulfate;

Fig. 5 represents that gabapentin enters colon (circle) and gabapentin lauryl sulfate salt complex (rhombus) when the intubate administration enters the colon of ligation through intravenous (triangle) with through the intubate administration, as the gabapentin plasma concentration (ng/mL) in the rat of time (with a hour expression) function;

Fig. 6 A represents gabapentin intravenous administration (triangle) and with the dosed administration of 5mg (circle), 10mg (square) and 20mg (rhombus) during to duodenum, as the gabapentin plasma concentration (ng/mL) in the rat of time (with a hour expression) function;

Fig. 6 B represent gabapentin lauryl sulfate salt complex intravenous administration (triangle) and with the dosed administration of 5mg (circle), 10mg (square) and 20mg (rhombus) to duodenum, as the gabapentin plasma concentration (ng/mL) in the rat of time (with a hour expression) function;

Fig. 6 C is after gabapentin (del) or gabapentin lauryl sulfate salt complex (circle) are administered to rat preduodenal, the curve chart of the dose function of gabapentin bioavailability (%);

Fig. 7 illustrates the exemplary osmotic dosage forms shown in the cutaway view;

Fig. 8 illustrates the another kind of exemplary osmotic dosage forms of gabapentin 1 dosage every day, and this dosage form comprises gabapentin-transhipment part complex or pregabalin-transhipment part complex, and the complex of the optional loading dose in the outer coating;

Fig. 9 illustrates an embodiment of 1 gabapentin every day (or pregabalin) dosage form, this dosage form had both contained gabapentin (pregabalin) and had also contained gabapentin (or pregabalin)-transhipment part complex, and the gabapentin (or pregabalin) of the optional loading dose of coating;

Figure 10 A-10C explanation delivers medicine to or the embodiment of predose, and the complex of gabapentin (or pregabalin)-transhipment part complex is included in (Figure 10 A) in the substrate, takes in the band-like portions after separating (Figure 10 C) that moves (Figure 10 B) and caused device in the abundant corrosion of substrate behind the gastrointestinal tract.

Describe in detail

I. definition

Preferably with reference to give a definition, accompanying drawing and exemplary bulletin provided herein understand the present invention.

Be meant one or more gabapentins-transhipment part or pregabalin-transhipment part complex with " compositions ", optional combine, and/or choose wantonly and combine with non-activity composition (for example pharmaceutically acceptable carrier, excipient, suspending agent, surfactant, disintegrating agent, binding agent, diluent, lubricant, stabilizing agent, antioxidant, penetrating agent, coloring agent, plasticizer etc.) with additional active pharmaceutical composition.

Be meant with " complex " and contain drug moiety and transhipment part by the associating material of tight ion pair key.Can distinguish medicine-partly-transhipment part complex and drug moiety and transhipment loose ion pair partly by the difference of in octanol/water, distributing behavior, have following characteristic relation;

Δ LogD=LogD (complex)-LogD (loose ion pair) 〉=0.15 (equation 1) wherein, D, partition coefficient (apparent partition coefficient) is to set pH (about usually pH=5.0 is to about pH=7.0) and at 25 ℃ of following all kinds drug moieties with transport partly in capryl alcohol ratio with the equilibrium concentration of identical type in water (deionized water).LogD (complex) is used for determining according to the drug moiety of this paper indication preparation and the complex of transhipment part.LogD (loose ion pair) is the physical mixture that is used for determining deionized water Chinese medicine part and transhipment part.For example, can determine to suppose the octanol/water apparent partition coefficient (D=C of complex (in deionized water 25 ℃) _{Capryl alcohol}/ C _Water) and with (mol/mol) physical mixture comparison in 1: 1 of transhipment part in 25 ℃ of deionized waters and drug moiety.If determine Log D and 1: 1 (mol/mol) physical mixture (D of supposition complex (D+T-) ⁺‖ T ^-) LogD between difference more than or equal to 0.15, so confirm that the supposition complex is according to complex of the present invention.In preferred embodiments, Δ Log D 〉=0.20, and more preferably Δ Log D 〉=0.25, and more preferably Δ Log D 〉=0.35 still.

Dosage form " be meant in medium, carrier, vehicle or be fit to deliver medicine to Pharmaceutical composition in their patient's of needs the device.

" medicine " or " drug moiety " refers to provide medicine, chemical compound or the medicament of some pharmacological action or the residue of these medicines, chemical compound or medicament when giving the patient.Be suitable for using in forming complex, medicine comprises acidity, alkalescence or amphion constituent (element), or acidity, alkalescence or amphion residue constituent.

" fatty acid " refers to that general formula is CH ₃(C _nH _x) any organic acid group of COOH, wherein hydrocarbon chain be saturated (x=2n, as Palmic acid, C ₁₅H ₃₁COOH) or undersaturated (x=2n-2, as oleic acid, CH ₃C ₁₆H ₃₀COOH).

" gabapentin " is meant that molecular formula is C ₉H ₁₇NO ₂And molecular weight is 171.24 1-(aminomethyl) Cyclohexaneacetic acid.The trade name that can buy on the market is Neurontin ^Its structure is shown in Fig. 2 A.

Be meant the digestive tract part that extends to anus from the under shed of stomach with " intestinal " or " gastrointestinal tract ", comprise small intestinal (duodenum, jejunum and ileum) and large intestine (ascending colon, transverse colon, descending colon, sigmoid colon and rectum).

" loose ion pair " be meant at physiology pH with in water environment, is easy to and may appears at a pair of ion that other loose pairing in the loose ion pair environment or free ions exchange mutually.With isotopic labeling and NMR or mass spectral analysis, can in experiment, find loose ion pair by the member and the another kind of ionic exchange that are recorded in loose ion pair in physiology pH and the water environment.Also available reversed-phase HPLC is found loose ion pair by being recorded in right being separated in of physiology pH and water environment intermediate ion in the experiment.Loose ion pair also can be called " physical mixture ", and by making ion pair physical mixed formation together in medium.

Be meant large intestine with " lower gastrointestinal tract " or " following G.I. road ".

Be meant the animal that needs treatment to get involved, preferred mammal, more preferably people with " patient ".

" closely ion pair " refers in physiological pH and aqueous environments, is not easy and the ion pair of other loose free ions to exchanging that can exist in tight ion pair environment.Tight ion pair can detect with experimental technique, does not promptly have exchange to record by an ion and another ion that uses tight ion pair in isotope-labelling method and NMR or mass spectrum record physiological pH and the aqueous environments.Closely ion pair can be found with experimental technique, promptly by using reversed-phase HPLC record physiological pH and aqueous environments intermediate ion that isolating lacking found.

" transhipment part " refers to the residue that can form the chemical compound of complex with medicine or form the chemical compound of complex with medicine, and wherein transhipment part is compared with the transhipment of complexation medicine not, has improved the transhipment of the transepithelial tissue of medicine.The transhipment part comprises hydrophobic part and acidity, alkalescence or amphion constituent or acidity, alkalescence or amphion residue constituent.In preferred embodiments, hydrophobic part comprises hydrocarbon chain.In one embodiment, the pKa of alkaline structure composition or alkaline residue constituent is preferably greater than about 8.0 greater than about 7.0.

" Pharmaceutical composition " refers to be fit to the patient's of needs said composition compositions.

Pregabalin is meant (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid).Pregabalin also can be called (S)-3-isobutyl group GABA or CI-1008 in the literature.The structure of pregabalin is shown in Fig. 2 B.

" constituent " refers to that (i) is the chemical group of macromole part and the chemical group that (ii) has recognizable chemical functional group.For example, acidic-group on the chemical compound or basic group are constituent.

" material " refers to have the chemical entities of concrete feature.

" residue constituent " refers to the constituent by modifying with the interaction or the reaction of another kind of chemical compound, chemical group, ion, atom etc.For example, carboxyl structure composition (COOH) interacts to form carboxylic acid sodium salt with sodium, and COO-is the residue constituent.

" upper gastrointestinal " or " going up the G.I. road " refers to comprise the gastrointestinal tract part of harmonization of the stomach small intestinal.

II. the formation of complex and evaluation

Indication as mentioned, the effective convulsion of gabapentin and alleviate neuropathic pain.Gabapentin shown in Fig. 2 A is a zwitterionic compound, pKa ₁Be 3.7 and pKa ₂Be 10.7.Its soluble in water and alkaline and acidic aqueous solution.The logarithm of partition coefficient in pH 7.4 (n-octyl alcohol/0.05M phosphate buffer) is-1.25.These characteristics, it is few to cause this chemical compound to absorb in gastrointestinal tract with its fact by the absorption of L-amino acid transport system discussed above.In the gastrointestinal tract from the pH of gastric about 1.2 to far-end ileum and large intestine about 7.5 pH the pH gradient (Evans, D.F. etc., Gut, 29: 1035-1041 (1988)) mean through the scope gabapentin of pH in the gastrointestinal tract and be with electric charge, also impel it to absorb less.Pregabalin shown in Fig. 2 B is the analog of gabapentin and the influence that is subjected to same characteristic features, causes the infra gastrointestinal absorption few.

Therefore, the invention provides the obvious chemical compound that contains gabapentin or pregabalin that lower gastrointestinal tract absorbs that improves on the one hand.This chemical compound is the complex of gabapentin and transhipment part or the complex of pregabalin and transhipment part.According to the general synthetic reaction flow process shown in Fig. 3 A, the salt of available medicine for example gabapentin or hydrochloric acid pregabalin prepares described chemical compound.In brief, make T among the medicine of the salt form that D+X-represents among Fig. 3 A and the figure ^-M ⁺The transhipment part combination of expression.Exemplary transhipment part is above being enumerated, and comprises fatty acid, soap, alkyl sulfate, benzenesulfonic acid, benzoic acid, fumaric acid and salicylic acid.Make these two kinds of materials in water in conjunction with forming loose ion pair (D+ ‖ X-represents among the figure), then as hereinafter will discuss be lower than solvation in the solvent of water at dielectric constant.This method causes forming gabapentin-transhipment part complex or pregabalin-transhipment part complex, and wherein the material in the complex associates with tight ion pair key, as being represented by D+T-among Fig. 3 A.

Fig. 3 B explanation forms the flow process of synthetic reaction more specifically of gabapentin (or pregabalin)-transhipment part complex.In this flow process, the transhipment part is expressed as the salt of alkyl sulfate, (R-SO ₄)-(Y) ⁺Alkyl sulfate and drug salts are mixed in water and are formed loose ion pair, in Fig. 3 B by D+ ‖ [(R-SO ₄)]-expression.The organic solvent that dielectric constant is lower than water adds in the aqueous solution of loose ion pair and extracts medicine-transhipment part complex, and its Chinese medicine and transhipment part are used D+[(R-SO in the drawings by tight ion pair key association ₄)]-expression.

Embodiment 1A provides the instantiation of preparation gabapentin-transhipment part complex step, and wherein this transhipment part is alkyl sulfate and alkyl sulfate more especially, shown in Fig. 3 C.For example, make gabapentin combine the salt form for preparing gabapentin, gabapentin with hydrochloric acid.Should be appreciated that other salt that can form gabapentin.Then, add for example lauryl sulfate ester of alkyl sulfate.In embodiment 1A, though with the sodium salt of lauryl sulfate ester, other salt also is suitable, for example alkylsurfuric acid potassium or alkylsurfuric acid magnesium.Gabapentin combines the ion pair that forms gabapentin and lauryl sulfate with sodium lauryl sulfate, as the loose ion pair between the material of representing among Fig. 3 C.The solvent that dielectric constant is lower than water adds the solution contain gabapentin and lauryl sulfate and fully mixes and its deposition of leaving.Gabapentin lauryl sulfate salt complex is extracted from solvent phase (nonaqueous phase), include but not limited to evaporation, distillation etc. with proper technology except that desolvating usually.

In embodiment 1A, form complex as exemplary transhipment part with alkyl sulfate (lauryl sulfate).Should be appreciated that lauryl sulfate only is equally applicable to be suitable as the material of transhipment other kind partly and the alkyl sulfate and the fatty acid of any carbon chain lengths as example and preparation process.For example, form the complex of gabapentin (or pregabalin) and different alkyl sulfates or fatty acid or their salt, wherein the alkyl chain in alkyl sulfate or the fatty acid contains from 6 to 18 carbon atoms, more preferably 8 to 16 carbon atoms and even more preferably 10 to 14 carbon atoms.Alkyl chain can be saturated or undersaturated.The exemplary saturated alkyl chain of fatty acid that design is used for preparing complex comprise butanoic acid (butyric acid, 4C); Valeric acid (valeric acid, 5C); Caproic acid (caproic acid, 6C); Sad (sad, 8C); N-nonanoic acid (n-nonanoic acid, 9C); Capric acid (capric acid, 10C); Dodecoic acid (lauric acid, 12C); Tetradecylic acid (myristic acid, 14C); Hexadecylic acid (Palmic acid, 16C); Heptadecanoic acid (heptadecanoic acid, 17C) and stearic acid (stearic acid 18C), wherein is the carbon atom number in popular name and the fatty acid in the garden bracket after the system name.Unsaturated fatty acid comprises oleic acid, linoleic acid plus linolenic acid, and all acid have 18 carbon atoms.Linoleic acid plus linolenic acid is a polyunsaturated acid.Exemplary gabapentin complex comprises Palmic acid gabapentin, oleic acid gabapentin, capric acid gabapentin, lauric acid gabapentin, lauryl sulfate gabapentin, decyl sulphuric acid gabapentin and myristyl sulphuric acid gabapentin.

The salt of exemplary alkyl sulfuric ester and alkyl sulfate (for example sodium, potassium, magnesium etc.) contains from 6 to 18 carbon atoms, and more preferably 8 to 16 and even more preferably 10 to 14 carbon atoms.Preferred alkyl sulfate comprises octyl sulfate, lauryl sulfate, sulphuric acid Semen Myristicae salt.Also can consider to form the complex of gabapentin or pregabalin and benzenesulfonic acid, benzoic acid, fumaric acid and salicylic acid or these sour salt.

Gabapentin and pregabalin are zwitterionic compounds, and the positive and negative charge group may be interacted.In one embodiment, selection can with the positive charge NH of gabapentin and pregabalin ₃ ⁺The interactional transhipment part of part is as discussing about Fig. 3 A-3C.Salt, alkyl sulfate (saturated or undersaturated) and their salt (particularly including sodium octyl sulfate, sodium decyl sulfate, sodium lauryl sulfate and sodium tetradecyl sulfate), benzenesulfonic acid and salt, benzoic acid and salt thereof, fumaric acid and salt thereof, salicylic acid and the salt thereof of fatty acid and they or contain the positive charge group complexation of other pharmaceutically acceptable chemical compound and their salt and the gabapentin or the pregabalin of at least one carboxyl.

In alternative embodiment, selection can with the interactional transhipment part of negative charge COO-group of gabapentin or pregabalin.For example, the negative charge group complexation of available aliphatic primary amine (saturated and undersaturated), diethanolamine, ethylenediamine, procaine, choline, trometamol, meglumine, magnesium, aluminum, calcium, zinc, alkyltrimethylammonium hydroxide, alkyltrimethylammonium bromide, benzalkonium chloride and benzethonium chloride and gabapentin and pregabalin.

Continue reference example 1A, prepare the complex of forming by gabapentin-lauryl sulfate with dichloromethane (chloroform).Dichloromethane is only as exemplary solvent, and the solvent of other solubilized transhipment part and medicine all is fit to.For example, fatty acid dissolves in chloroform, benzene, cyclohexane extraction, ethanol (95%), acetic acid and methanol.Capric acid, lauric acid, myristic acid, Palmic acid and stearic dissolubility (g/L) are as shown in table 1 in these solvents.

Table 1: at the dissolubility (g/L) of 20 ℃ of fatty acids

Fatty acid (carbon number)	Chloroform	Benzene	Cyclohexane extraction	Acetone	95% ethanol	Acetic acid	Methanol	Acetonitrile
									Capric acid (10)	3260	3980	3420	4070	4400	5670	5100	660
Lauric acid (12)	830	936	680	605	912	818	1200	76
									Myristic acid (14)	325	292	215	159	189	102	173	18
Palmic acid (16)	151	73	65	53.8	49.3	21.4	37	4
									Stearic acid (18)	60	24.6	24	15.4	11.3	1.2	1	＜1

In one embodiment, being used to form the used solvent of complex is the solvent of dielectric constant less than water, preferred at least less than 1/2nd of the dielectric constant of water, more preferably at least less than 1/3rd of the dielectric constant of water.Dielectric constant is the measurement method of solvent polarity, and the dielectric constant of exemplary solvent is as shown in table 2.

Table 2: the feature of exemplary solvent

Solvent	Boiling point, ℃	Dielectric constant
			Water	100	80
Methanol	68	33
			Ethanol	78	24.3
The 1-propanol	97	20.1
			The 1-butanols	118	17.8
Acetic acid	118	6.15
			Acetone	56	20.7
Methyl ethyl ketone	80	18.5
			Ethyl acetate	78	6.02
Acetonitrile	81	36.6
			N, dinethylformamide (DMF)	153	38.3
Dimethyl sulfoxine (DMSO)	189	47.2
			Hexane	69	2.02
Benzene	80	2.28
			Diethyl ether	35	4.34
Oxolane (THF)	66	7.52
			Dichloromethane	40	9.08
Carbon tetrachloride	76	2.24

Aqueous solvent, methanol, ethanol, 1-propanol, 1-butanols and acetic acid are for having the hydrogen atom polar aprotic solvent that is connected to electronegative atom (being generally oxygen atom).Solvent acetone, ethyl acetate, methyl ethyl ketone and acetonitrile are dipolar aprotic solvent, in one embodiment, preferably use in forming gabapentin (or pregabalin)-transhipment part complex.Dipolar aprotic solvent does not comprise the OH key, but because the multiple bond between carbon and oxygen or the nitrogen generally has the dipole moment of big key.Most of dipolar aprotic solvents comprise the two keys of C-O.The dielectric constant of the dipolar aprotic solvent of record is at least less than 1/2nd of water in table 2.

Fig. 3 D represents to form the synthetic reaction flow process of lauryl sulfate pregabalin complex.As described in the embodiment 1B, make pregabalin and aqueous solution of hydrochloric acid be mixed with the salt form of pregabalin, for example hydrochloric acid pregabalin.Should be appreciated that other salt that can form pregabalin.Then, add alkyl sulfate, for example lauryl sulfate.Though what Fig. 3 D showed is the sodium salt of lauryl sulfate ester, other salt also is fit to, for example alkylsurfuric acid potassium or alkylsurfuric acid magnesium.The hydrochloric acid pregabalin mixes the ion pair that forms pregabalin and lauryl sulfate with sodium lauryl sulfate, be expressed as the loose ion pair between the described material in Fig. 3 D.The solvent that dielectric constant is lower than water adds in the solution of the ion pair contain pregabalin and lauryl sulfate and thoroughly mixes and its deposition of leaving.From solvent phase (nonaqueous phase), extract pregabalin-lauryl sulfate salt complex, remove with proper technology usually and desolvate, include but not limited to evaporation, distillation etc.

Analyze gabapentin-lauryl sulfate salt complex of describing formation as embodiment 1A with Fourier transform infrared spectroscopy (FTIR).FTIR/ATR methodology method is hereinafter partly described.For comparing, also produce the FTIR/ATR spectrum of 1: 1 mol ratio physical mixture (making two components be dissolved in methanol and become solid film) of gabapentin, sodium lauryl sulfate and gabapentin and sodium lauryl sulfate, and the result is shown in Fig. 4 A-4D at air drying.The spectrum of gabapentin and is indicated peak corresponding to NH and COO part shown in Fig. 4 A.The spectrum of sodium lauryl sulfate is shown in Fig. 4 B, and at 1300-1200cm ^-1Between observe main bimodal corresponding to S-O part.Gabapentin and sodium lauryl sulfate at 1: 1 molar mixture in the water shown in Fig. 4 C, and the obviously obviously decay and observe the S-O peak (1300-1200cm of sodium lauryl sulfate of characteristic peak of gabapentin ^-1) broadening.Fig. 4 D shows the FTIR spectrum of the complex that the step with embodiment 1A forms, and wherein disappears corresponding to 2 peaks of the COO-group of gabapentin and is substituted by the peak of the COOH group of gabapentin lauryl sulfate salt complex, shows the electric charge of having blocked COO-.The N-H that observes gabapentin in gabapentin lauryl sulfate spectrum partly is out of shape (has 15cm ^-1Displacement).The N-H group is protonated in the complex that the offset table open-birth of N-H key bands of a spectrum becomes.As what in the spectrum of gabapentin complex, show, the 1250cm that expression S-O absorbs in sodium lauryl sulfate spectrum ^-1The peak shift 30cm at place ^-1, the interaction of the sulfate groups of prompting gabapentin and sodium lauryl sulfate.FTIR scanning shows that the complex of gabapentin formation is different from the physical mixture of two kinds of components.

Do not wish to be subjected to the concrete understanding of mechanism to fetter, the inventor's the reasons are as follows.When loose ion pair places the polar solvent environment, suppose the space that polar solvent molecule meeting insertion itself is occupied by ionic bond, thereby impel the ion of bonding to separate.Can form the solvation shell around the free ion, the solvation shell comprises static and is bonded to polar solvent molecule on the free ion.Thereby this solvation shell prevents this free ion and another free ion and forms any form, but is the ionic bond of loose ion pair.Under the polytype counter ion was present in condition in the polar solvent, any specific loose ion pair may be to the counter ion competing phase to sensitivity.

This effect is more obvious when polarity strengthens, and polarity is represented with the dielectric constant of solvent.Based on Coulomb's law, electrically charged (q1) and (q2) and the power between two kinds of ions that separated by the distance (r) in dielectric constant (e) medium be: $F=-\frac{q_1{\mathrm{<figure-callout\; id="2"\; label="q"\; filenames="A20048003917100481.png,A20048003917100491.png"\; state="\{\{state\}\}">q</figure-callout>}}_2}{4{\mathrm{\&pi;\&epsiv;}}_0{\mathrm{\&epsiv;r}}^2}$ (equation 2)

ε wherein ₀Be the spatial dielectric constant.Equation shows the importance of dielectric constant (ε) to loose ion pair stability in the solvent.In the aqueous solution of high-k (ε=80), if the ionic combination of hydrone attack and separate opposite charged ion, then electrostatic attraction is significantly reduced.

Therefore, the high dielectric constant solvent molecule can attack ionic bond and final this key that destroys near in a single day being present in ionic bond.So the ion of this not bonding freely moves in solvent.These property definitions are loose ion pair.

Closely the formation of ion pair is different with loose ion pair, thereby has the character that is different from loose ion pair.Form tight ion pair by the number that reduces polar solvent molecule in two interionic bonding spaces.This makes ion closely move together, and forms than the remarkable stronger key of loose ion pair key, but still thinks ionic bond.More completely open herein, use the polarity solvent littler to obtain tight ion pair with the embedding that reduces the interionic polar solvent than water.

As for the other discussion of loose and tight ion pair, see D.Quintanar-Guerrero etc., Pharm.Res., 14(2): 119-127 (1997).

Also can use the difference between the loose and tight ion pair of chromatographic process observation.Use reversed phase chromatography, Yu Buhui to separate under the condition of tight ion pair and can easily separate loose ion pair.

Also can be according to the present invention by selecting cation and the stronger chemical bond of anion prepared at concentrations relative to each other.Be under the situation of water for example, can select cation (alkali) and anion (acid) to reach stronger attracting each other at solvent.More weak if desired key then can be selected more weak attraction.

Stride the transhipment of this class film in order to understand molecule, the biomembrane partial simulation can be become the ground floor (first order) of approximate lipid bilayer.Because unsuitable portioning, the transhipment (opposite with active transport etc.) of striding the lipid bilayer part is unfavorable for ion.Each researcher these ionic electric charges of having advised neutralizing can increase transmembrane transport.

In " ion pair " theory, the ion medicine part is matched with " hiding " electric charge with transhipment part counter ion and is made the gained ion pair easier to be mobile in lipid bilayer.This method has caused a large amount of concerns and research, especially pays close attention to the raising per os and gives the absorption that medicine is striden enterocyte.

Although ion pair has caused many concerns and research, never obtain many successes.For example, the ion pair of finding two kinds of antiviral compounds causes to absorb and increases, be not because the effect of ion pair transcellular transport but since to the effect of monolayer integrity (J.Van Gelder etc., Int.J.of Pharmaceutics, 186: 127-136 (1999).The author infers that the formation of ion pair may not be very effective to the transepithelial cell traffic that improves charged hydrophilic compounds because find in vivo can destroy the beneficial effect of counter ion with other ionic competitions.Other authors have pointed out that the absorption experiment of ion pair always do not point to clear and definite mechanism (D.Quintanar-Guerrero etc., Pharm.Res., 14 (2): 119-127 (1997)).

The problem that the inventor has been surprised to find that these ion pair absorption experiment for they use loose ion pair rather than closely ion pair experimentize.Really, disclosed in the art many ion pair absorbs absorption experiment even does not clearly distinguish loose ion pair and the tight difference between the ion pair.The technical staff in fact has to by looking back the disclosed loose ion pair in open method district office of preparation ion pair, and indicates at loose ion pair but not closely ion pair of these disclosed preparation methoies.Loose ion pair is allowed the competition of counter ion relatively, and the cracking in conjunction with the ionic bond of loose ion pair by solvent mediation (as the water mediation) takes place easily.Therefore, when the drug moiety of ion pair arrives the membranous wall of enterocyte, can or cannot with the transhipment part with free ion to combining.Exist the probability of ion pair to depend on maintenance ion ionic bond together near the membranous wall, but depend on two kinds of ions local concentration separately more.When they during near the enterocyte membranous wall, if two parts do not have combination, the infiltration rate of non-complexation drug moiety may not can be subjected to the influence of non-complexation transhipment part.So compare with giving drug moiety separately, loose ion pair may be to absorbing only limited influence.

On the contrary, complex of the present invention has more stable key in the presence of polar solvent such as water.So inventor's inference, by forming complex drug moiety and transhipment part in close membranous wall, these parts will more may be associated with the ion pair form.This association can increase the electric charge of above-mentioned part by the chance of hidden (buried), makes the easier cell membrane that passes through of gained ion pair.

In one embodiment, complex comprises tight ion pair key between drug moiety and transhipment part.Discuss as this paper, closely ion pair is more stable than loose ion pair, thereby increases drug moiety and transport part near membranous wall the time, and described part can be with the associating probability of ion pair form.This association can increase the electric charge of above-mentioned part by hidden chance, makes the easier cell membrane that passes through of complex of tight ion pair bonding.

Should note drug moiety with respect to non-complexation, complex of the present invention can improve in whole gastrointestinal absorption, and just do not improve the absorption of lower gastrointestinal tract, because expect that general improvement of this complex strides the cell passage transhipment, and just do not improve the transhipment of lower gastrointestinal tract.For example, if drug moiety is for mainly coming across the proteic substrate of active transport in the upper gastrointestinal, then the complex that is formed by drug moiety still can be used as the substrate of transport protein.Therefore, total transhipment can be for being added the improved transhipment amount sum due to the cell of striding provided by the present invention by transport protein.In one embodiment, complex of the present invention improves at upper gastrointestinal, lower gastrointestinal tract, and the absorption at upper gastrointestinal and lower gastrointestinal tract two positions.

In supporting the research that the present invention carries out, identify that with (flush-ligated) colon models of rat flushing ligation gabapentin in the body-lauryl sulfate salt complex infra gastrointestinal absorbs.As described in the embodiment 2, with the form of gabapentin-lauryl sulfate salt complex or pure gabapentin with the dosage intubate of 10mg gabapentin/rat to the colon of testing the rat ligation (every group of n=3).The 3rd group of rat (n=3) intravenous gives 1mg gabapentin.Regularly extract blood sample and analyze gabapentin concentration.Data as shown in Figure 5.

With reference to Fig. 5, the initial plasma concentration of the gabapentin of intravenous administration (triangle) is high and descend rapidly through concentration after preceding 15 minutes.Visible drug absorption is slow when gabapentin is injected (circle) administration with colonic.On the contrary, when medicine with gabapentin-lauryl sulfate complex form (rhombus) when giving lower gastrointestinal tract, visible medicine absorbs rapidly, intubate was observed Cmax after 1 hour.

The pharmacokinetic parameter of this research is as shown in table 3.Determine area under a curve (AUC) according to the 1mg gabapentin/rat of every kind of gabapentin dosage forms from 0 of time to time infinity, wherein by supposition log-linear decay unlimitedness estimated time.The gabapentin bioavailability is represented with the percent of the gabapentin concentration that intravenous administration produces.

Table 3

Medicament forms (route of administration)	AUC∞(ng·h/mL-mg)	Bioavailability (%)
			Gabapentin (intravenous)	6090.3	100
Gabapentin (colon)	301.4	4.9
			Gabapentin lauryl sulfate salt complex (colon)	3854.1	63.3

When the complex of gabapentin and lauryl sulfate gave lower gastrointestinal tract with complex form, the bioavailability of described complex was obviously improved with respect to pure medicine, thereby was clear that complex provides enhanced colon to absorb.The bioavailability of gabapentin-lauryl sulfate salt complex has been improved 13 times with respect to pure bioavailability of medicament.Therefore, the present invention has designed the chemical compound of the complex of being made up of gabapentin (or pregabalin) and transhipment part, wherein the colon with respect to gabapentin (or pregabalin) absorbs, this complex provides at least 5 times, more preferably at least 10 times and more preferably at least 12 times colon absorption, and this can be proved by gabapentin (or pregabalin) bioavailability that gabapentin (or pregabalin) plasma concentration is determined.Therefore, promote that obviously gabapentin (or pregabalin) per rectum is absorbed into blood during with gabapentin (or pregabalin)-transhipment part complex form administration when gabapentin (or pregabalin).

As described in embodiment 3, gabapentin or gabapentin-lauryl sulfate salt complex be put in carry out another research in the rat preduodenal.With the dosed administration of 5mg/ rat, 10mg/ rat, 20mg/ rat and extract blood sample, be that function is determined gabapentin concentration with time.Another group experimental animal intravenous is accepted gabapentin or gabapentin-lauryl sulfate salt complex.The result is shown in Fig. 6 A-6C.

Fig. 6 A show pure gabapentin intravenous (triangle) and the animal of handling with 5mg (circle), 10mg (square) and 20mg (rhombus) dosage intraduodenal administration in, the gabapentin plasma concentration of representing with ng/mL.The animal that enters duodenal administration through intubate observes the increase that increases blood concentration with dosage.The lower plasma drug level of animal that nature, intravenous are handled (triangle) is because lower drug dose.

Fig. 6 B shows gabapentin-lauryl sulfate salt complex intravenous (triangle) and the result who directly gives duodenal animal with 5mg (circle), 10mg (square) and 20mg (rhombus).Be lower than the animal of handling though accept the absolute blood concentration of gabapentin-lauryl sulfate salt complex animal with gabapentin, but data show is with respect to the absorption of pure medicine, the gabapentin that absorbs from complex has increased, and part may be because L-amino acid transport system is unsaturated and/or complex has increased transhipment by other mechanism.Can know in Fig. 6 A and 6B and see between 5mg and the 10mg dosage and the comparison of haemoconcentration between 10mg and the 20mg dosage that wherein gabapentin is bigger with the haemoconcentration increase that dosage increases with the complex form administration.

Fig. 6 C shows that gabapentin gives the bioavailability percent of rat preduodenal with pure medicine (del) or gabapentin lauryl sulfate salt complex (circle).Bioavailability percent is definite with respect to the gabapentin intravenous administration.At 20mg dosage, gabapentin-lauryl sulfate salt complex shows higher bioavailability with respect to pure medicine.The bioavailability that increases at the higher dosage place may be because the absorption that complex provides increases, and wherein absorbs at gastrointestinal to be not limited to the absorption to complex by L-amino acid transport system, but also takes place by striding cell and parietal cell mechanism.

Table 4 shows the pharmacokinetic analysis of this research, wherein determines from 0 to 4 hour area under a curve, and is standardized as 1mg dosage gabapentin/rat.Measurement data supposition in 3 hours is with respect to the log-linear decay of 4 hours some gabapentins data (iv) in the past.Bioavailability percent is the percent that gives the bioavailability of gabapentin with respect to intravenous.

Table 4

Medicament forms	Dosage (mg/kg ± s.d.)	AUC(0～4h，ng·h/ ml-mg±s.d.) *	Bioavailability (%)
				Gabapentin (intravenous)	1	2727.1±259.1	100.0
Gabapentin (duodenum)	14.8±0.1	1705.2±257.2	62.5±9.4
				Gabapentin (duodenum)	30.6±1.7	1205.7±276.3	44.2±10.1
Gabapentin (duodenum)	59.8±1.7	726.1±223.9	26.2±8.2
				Lauryl sulfate gabapentin (duodenum)	14.0±0.1	1604.3±479.1	58.8±17.6
Lauryl sulfate gabapentin (duodenum)	29.1±1.1	1182.2±267.9	43.3±9.8
				Lauryl sulfate gabapentin (duodenum)	58.1±2.3	1033.9±88.9	37.9±3.3

^*Be standardized as 1mg gabapentin/kg dosage

AUC and bioavailability data show when medicine with gabapentin-when transhipment part complex form provides, the colon of gabapentin absorbs to increase with dosage and improves.

Though experimental data is based on gabapentin, should be appreciated that this discovery extends to pregabalin, the analog of gabapentin.Embodiment 4 and 5 describes the pregabalin-systemic method of lauryl sulfate salt complex body of determining.

III. exemplary dosage forms and using method

Above-described complex is provided at gastrointestinal tract and particularly enhanced absorption in the rat lower gastrointestinal tract.Now will describe the complex dosage form and use complex and the method for its enhanced colon absorption treatment.Should be appreciated that dosage form described below is an example.Should also be appreciated that described dosage form is equally applicable to gabapentin, pregabalin or their mixture.Though in the discussion hereinafter, what mention is gabapentin; But should be appreciated that this discussion also is applicable to pregabalin.

Many dosage forms are applicable to gabapentin-transhipment part complex.As discussed above, this dosage form provides every day 1 dosage to reach at least about 12 hours, more preferably at least 15 hours and still more preferably at least about 20 hours therapeutic effect.Can be according to the design configurations and the preparation dosage form of the gabapentin of any release needs dosage.Usually, this dosage form per os gives, the tablet or the capsule of its size and the similar routine of shape.But can prepare the dosage form that per os gives according to one of various method.For example, this dosage form can be made into diffusion system and (comprises the associating as " regularly micropill (tiny time pills) " and pearl and stromatolysis system and diffusion/dissolution system and ion exchange resin system as storage storehouse device (reservoirdevice) or matrix device, dissolution system as wrapping capsular dissolution system, as Remington ' s Pharmaceutical Sciences, 18 ^ThEd., described in the pp.1682-1685 (1990).

The instantiation that is applicable to the dosage form of gabapentin-transhipment part complex is an osmotic dosage form.Usually, osmotic dosage form utilizes osmotic pressure to produce driving force, and liquid to small part is infiltrated in the compartment that is formed by semi-permeable wall, and described wall permission liquid freely spreads but do not allow medicine or penetrating agent (if existence) freely to spread.The advantage of osmosis system does not rely on pH for their running, thereby in whole time expand section, though when this dosage form through gastrointestinal tract and when running into different microenvironment with remarkable different pH value, continue to turn round with the speed of infiltration decision.At Santus and Baker, " Osmotic drug delivery:a review of the patentliterature (release of osmotic drug: the review of patent documentation), " Journal of ControlledRelease, 35: can find the commentary of relevant these dosage forms among the 1-21 (1995).Also describe osmotic dosage form in following United States Patent (USP) in detail, each document is attached to herein by reference: Nos.3,845,770,3,916,899,3,995,631,4,008,719,4,111,202,4,160,020,4,327,725,4,519,801,4,578,075,4,681,583,5,019,397 and 5,156,850.

Be presented at the exemplary dosage forms of mentioning with primary osmotic pump (elementary osmoticpump) dosage form in the art among Figure 11.Dosage form 20 shown in the profile also is mentioned with the primary osmotic pump dosage form, by around with form around the semi-permeable wall 22 of interior compartment 24.Interior compartment comprises single component layer, is referred to herein as medicine layer 26, and this medicine layer comprises the mixture of gabapentin-transhipment part complex 28 and selected excipient.Adjust excipient so that the osmotically active gradient to be provided, this gradient is used for attracting liquid to enter through wall 22 from the external world, just forms releasable gabapentin-transhipment part complex preparation in case soak into liquid.Excipient can comprise suitable suspensoid (being also referred to as pharmaceutical carrier 30 herein), binding agent 32, lubricant 34 and be called the osmotically active agent of penetrating agent 36.The exemplary raw material of each composition in these compositions is provided below.

The semi-permeable wall 22 of osmotic dosage form can see through the liquid of outside process, as water and biofluid, but basically can not be through the composition of process in the interior compartment.The raw material that is used to form wall is not erodible in essence between the operating period and is insoluble to biological fluid substantially in dosage form.The representative polymers that forms semi-permeable wall is drawn together homopolymer and copolymer, as cellulose esters, cellulose ether and cellulose esters-ether.Channel modulators can form raw material with wall to be mixed to regulate the permeability for liquids of wall.For example, it usually is hydrophilic substantially that the infiltration of liquid such as water is produced the reagent that significantly increases, and is hydrophobic substantially and the infiltration of water is produced significantly reduced those reagent.The exemplary path regulator comprises polyhydric alcohol, poly alkylene glycol (glycol), poly alkylene glycol (polyalkylenediols), aklylene glycol polyester etc.

On-stream, because the osmotically active agent exists, the osmotic gradient of striding wall 22 causes that gastric juice passes wall and is absorbed, and makes the medicine layer swelling and form the releasable preparation (as solution, suspensoid, serosity or other flowable composition) that contains gabapentin-transhipment part complex in interior compartment.Releasable gabapentin when liquid continues to enter interior compartment-transhipment part complex preparation discharges by outlet 38.Even when dosage form discharged, liquid still continued to be inhaled into inner chamber at the preparation that contains complex, continue to discharge thereby drive.By this way, gabapentin-transhipment part complex discharged in mode stable, that continue in the time period of extending.

Embodiment 6A describes preparation gabapentin-transhipment part complex and embodiment 6B describes the dosage form as shown in Figure 7 for preparing pregabalin-transhipment part complex.

Fig. 8 is the sketch of another kind of exemplary osmotic dosage forms.At United States Patent (USP) the 4th, 612,008,5,082,668 and 5,091, describe this dosage form in detail in No. 190, above patent is attached to herein by reference.Briefly, the dosage form 40 of sectional view demonstration has the semi-permeable wall 42 of interior compartment of defining 44.Interior compartment 44 comprises the double-deck compressed core (core) with medicine layer 46 and promoting layer 48.Will describe below, promoting layer 48 is for being seated in transfer percolation (displacement) compositions in the dosage form, and promoting layer expands between the operating period, and the raw material that forms medicine layer is discharged from dosage form as exporting 50 through one or more outlets.Promoting layer can place the arrangement layering that contacts with medicine layer, and as shown in Figure 8, perhaps promoting layer can have the one or more intermediate layers that isolate promoting layer and medicine layer.

Medicine layer 46 contains and the excipient of selecting (for example those that above discuss with reference to figure 7) blended gabapentin-transhipment part complex.Exemplary dosage forms can comprise by ferrous-medicine layer that the lauryl complex is formed, as the poly(ethylene oxide) of carrier, as the sodium chloride of penetrating agent, as the hydroxypropyl emthylcellulose of binding agent with as the magnesium stearate of lubricant.

Promoting layer 48 comprises the osmotically active composition, as drawing water liquid or biofluid and swollen one or more polymer, is called osmopolymer in the art.Osmopolymer is the hydrophilic polymer of swellable, with water and aqueous biological fluids interaction, swelling or be extended to largely, generally demonstrates the increase of 2-50 times of volume.Osmopolymer can be noncrosslinking or crosslinked, and osmopolymer is lightly crosslinked at least producing polymer network in preferred embodiments, and the very big and entanglement of this network is discharged from dosage form so that be not easy between the operating period.The examples of polymer that can be used as osmopolymer provides in the reference of foregoing detailed description osmotic dosage form.General osmopolymer is a polyalkylene oxide, and as poly(ethylene oxide) and poly-carboxymethyl cellulose alkali salt (poly (alkali carboxymethylcellulose)), wherein alkali is sodium, potassium or lithium.Other excipient such as binding agent, lubricant, antioxidant and coloring agent also can be included in the promoting layer.In the use, when liquid when semi-permeable wall absorbs, the osmopolymer swelling also promotes medicine layer and impels medicine to discharge through outlet from dosage form.

Promoting layer also can comprise the composition of mentioning with binding agent, is generally cellulose or polyvinyl as poly-positive vinylamide, poly-positive vinyl acetamide, polyvinyl pyrrolidone, poly-positive vinyl caprolactone (caprolactone), poly-positive vinyl-5-N-methyl-2-2-pyrrolidone N-etc.Promoting layer also can comprise lubricant such as sodium stearate or magnesium stearate, and the antioxidant that suppresses the composition oxidation.Representative antioxidant includes, but are not limited to the mixture and the butylated hydroxytoluene of ascorbic acid, ascorbic palmitate, butylated hydroxyanisole, 2-and 3-t-Butyl-4-hydroxyanisole.

Penetrating agent also can mix the medicine layer and/or the promoting layer ester of osmotic dosage form.The osmotically active gradient of striding semi-permeable wall is set up in the existence of penetrating agent.Exemplary penetrating agent comprises salt such as sodium chloride, potassium chloride, lithium chloride etc., and sugar reaches carbohydrate as Raffinose, sucrose, glucose, lactose.

Continuation is with reference to figure 8, and dosage form can be chosen wantonly and comprise that the outer coating (not shown) is used for according to dosage coloured marking dosage form or the release immediately of gabapentin, pregabalin or other medicines is provided.

In use, water is striden wall and is flow through and enter promoting layer and medicine layer.The promoting layer imbitition also begins to expand, and then advances medicine layer 44 to make the material in this layer enter gastrointestinal tract through the outlet discharge.Promoting layer 48 is designed imbitition and continues to expand, thereby makes dosage form continue from start to finish medicine is discharged from medicine layer in gastrointestinal tract.Like this, dosage form provides gabapentin-transhipment part complex to gastrointestinal tract and continues 15 to 20 hours, or run through basically dosage form by gastrointestinal whole during.Because gabapentin-transhipment part complex all absorbs at upper and lower gastrointestinal tract, thus this dosage form by gastrointestinal tract during the administration of this dosage form gabapentin is passed in the blood flow.

Another kind of exemplary dosage forms as shown in Figure 9.Osmotic dosage form 60 has trilaminar core 62, and this core comprises three layers: ground floor gabapentin 64, second layer gabapentin-transhipment part complex 66 and be called the 3rd layer 68 of promoting layer.At United States Patent (USP) the 5th, 545,413,5,858,407,6,368,626 and 5,236, describe the dosage form of the type in No. 689 in detail, these patents are attached to herein by reference.As in embodiment 7, pointing out, three layers of dosage form ground floor of preparation contain 100 of 85.0wt% gabapentin, 10.0% weight, the poly(ethylene oxide) of 000 molecular weight, about 35,000 to 40,000 the polyvinylpyrrolidone of 4.5wt% molecular weight and 0.5wt% magnesium stearate.The second layer comprises 93.0wt% gabapentin-transhipment part complex (press embodiment 1A and describe preparation), 5.0wt% molecular weight 5,000,000 poly(ethylene oxide), about 35,000 to 40,000 the polyvinylpyrrolidone of 1.0wt% molecular weight and 1.0wt% magnesium stearate.

Promoting layer is made up of the poly(ethylene oxide) of 63.67% weight, the sodium chloride of 30.00% weight, the ferrum oxide of 1.00% weight, the hydroxypropyl emthylcellulose of 5.00% weight, the butylated hydroxytoluene of 0.08% weight and the magnesium stearate of 0.25% weight.Semi-permeable wall is made up of the cellulose acetate and the 20.0% poly(ethylene oxide)-poly(propylene oxide) copolymer of 80.0% weight with 39.8% acetyl content.

Can determine the dissolution rate of dosage form (for example those dosage forms shown in Fig. 7-9) according to the step that embodiment 8 proposes.Usually, the being released in contact of pharmaceutical preparation from dosage form begins after the water environment, wherein depends on dosage form, contains the pharmaceutical preparation of gabapentin or gabapentin-transhipment part complex.For example, in the dosage form that Fig. 7 represents, gabapentin-transhipment part complex discharges and continues the life period of this device after the contact water environment.The dosage form that Fig. 9 represents discharges the gabapentin in the contiguous medicine layer that exports at first, then discharges gabapentin-transhipment part complex.

Figure 10 A-10C illustrates another kind of exemplary dosage forms known in the art, at U.S. Patent number 5,534, description is arranged in 263,5,667,804 and 6,020,000, and it is attached to herein by reference especially.In brief, Figure 10 A shows the cross-sectional view of taking in gastrointestinal tract dosage form 80 before.This dosage form comprises cylindrical substrate 82, and it contains gabapentin-transhipment part complex.The two ends 84,86 of substrate 82 are preferably the circular convex shape so that guarantee light picked-up.Be with 88,90 and 92 with one heart around cylinder substrate, these bands are formed by the material that is insoluble to relatively in the aqueous environment.Enumerated suitable material among patent of Zhu Minging and the following embodiment 9 in the above.

After dosage form 80 is taken in, begin ablations with substrate 82 zones between 88,90,92, shown in Figure 10 B.The erosion of substrate starts gabapentin-transhipment part complex and is released in the gastrointestinal liquid environment.When dosage form continues when gastrointestinal tract transport, substrate continuation ablation is shown in Figure 10 C.At this moment, the ablation of substrate has developed into the degree that dosage form is broken into three fragments 94,96,98.Ablation is proceeded until the substrate of each fragment part fully by ablation.Be with 94,96,98 can discharge from gastrointestinal tract thereafter.

Should be appreciated that dosage form that Fig. 7-10 describes only as design and gabapentin-transhipment part complex can be released into the example of the multiple dosage form of lower gastrointestinal tract.The technical staff of pharmaceutical field can confirm other suitable dosage form.

On the other hand, the compositions that the invention provides the complex by containing gabapentin and transhipment part gives patient's method with gabapentin, the feature of this complex be gabapentin (or pregabalin) with transhipment partly between tight ion pair key.Common oral administration administration will contain complex and pharmaceutically acceptable vectorial compositions gives the patient.

Consider dosage form and required result, the dosage that gives is generally regulated according to patient's age, body weight and disease.In general, the dosage form of gabapentin-transhipment part complex and compositions are with gabapentin (Neurontin ^) treat the amount administration of recommending, as in Physician ' s DeskReference (doctor's handbook), proposing.The typical doses of Taking Control of Epilepsy patient's epilepsy is 900-1800mg every day.The typical doses that is used for alleviating neuropathic pain be every day 600-3600mg (Backonja, M., Clinical Therapies, 23(1) (2003)).Should be appreciated that these dosage ranges represent approximate extents, and the absorption of the increase that provides of complex will change the dosage that needs.

About pregabalin, also will be according to patient's age, body weight and state, the result who takes dosage form and needs into consideration adjusts the dosage of administration.In general, provide every day at least about 300mg dosage and increase as required to alleviate perception pain.Alleviating of pain measured in available digital pain ranking evaluation, for example Short-Form McGill Pain Questionnaire (Dworkin, R.H. etc., Neurology, 60: 1274 (2003)).

From aforementioned content as seen, various purpose of the present invention and feature are met.The complex (gabapentin (or pregabalin) associates by non-covalent tight ion pair key with the transhipment part) that contains gabapentin or pregabalin and transhipment part promotes that medicine absorbs at gastrointestinal.This complex prepares with new method, and wherein gabapentin or pregabalin contact with being dissolved in the transhipment part (for example alkyl sulfate or fatty acid) that polarity is lower than the solvent of water, for example can pass through provable its low polarity of low-k.Medicine makes between medicine (gabapentin or pregabalin) and the transhipment part with contacting of transhipment part-solvent mixture and forms complex, and wherein both associate by tight ion pair key.

IV. embodiment

Following examples further specify the present invention described herein, never plan to limit the scope of the invention.

Method:

1.FTIR: on Perkin-Elmer Spectrum 2000 spectroscopic systems that are equipped with attenuated total reflectance (ATR) adnexa and cooled with liquid nitrogen MCT (cadmium mercury telluride) detector, carry out the inspection of Fourier transformation spectrophotometric spectra.

Embodiment 1

Preparation gabapentin-transhipment part complex and pregabalin-transhipment part complex

Preparation gabapentin-transhipment part complex

1. prepare the solution of 0.5mL 36.5% hydrochloric acid (5mmol HCl) in the 25mL deionized water.

2. 5mmol gabapentin (0.86g) is added in the solution of step 1.In stirring at room mixture 10 minutes.Form gabapentin.

3. 5mmol sodium lauryl sulfate (1.4g) is added in the aqueous solution of step 2.In stirring at room mixture 20 minutes.

4. the 50mL dichloromethane is added in the solution of step 3.In stirring at room mixture 2 hours.

5. the mixture with step 4 is transferred to separatory funnel and allows its precipitation 3 hours.Form biphase, low level phase dichloromethane and high-order water mutually.

In the separating step 5 high-order mutually with low level mutually.Reclaim low level phase dichloromethane and dichloromethane is evaporated to drying, then in 40 ℃ of vacuum drying ovens dry 4 hours in room temperature.Obtain the complex (1.9g) of gabapentin-lauryl sulfate.Gross production rate is 87% for the theoretical amount of calculating with gabapentin and sodium lauryl sulfate initial amount.

Preparation pregabalin-transhipment part complex

1. prepare the solution of 0.5mL 36.5% hydrochloric acid (5mmol HCl) in the 25mL deionized water.

2. 5mmol pregabalin (0.80g) is added in the solution of step 1.In stirring at room mixture 10 minutes.Form the hydrochloric acid pregabalin.

3. 5mmol sodium lauryl sulfate (1.4g) is added in the aqueous solution of step 2.In stirring at room mixture 20 minutes.

4. the 50mL dichloromethane is added in the solution of step 3.In stirring at room mixture 2 hours.

5. the mixture with step 4 goes to separatory funnel and allows its precipitation 3 hours.Form biphase, low level phase dichloromethane and high-order water mutually.

In the separating step 5 high-order mutually with low level mutually.Reclaim low level phase dichloromethane and dichloromethane is evaporated to drying, then in 40 ℃ of vacuum drying ovens dry 4 hours in room temperature.Obtain the complex (2.1g) of pregabalin-lauryl sulfate.

Embodiment 2

Absorb with colon in the body of the colon models of rat flushing ligation

Adopting known usually is the animal model of " colon models of flushing ligation " or " model of colonic ligation ".With the 0.3-0.5kg Sprague-Dawley male rat after fasting anesthesia and separate sections near colon.The Excreta raw material of flushing colon.With the two ends ligation of this colon sections, simultaneously conduit is placed in the chamber and takes out in the abdomen and place on the skin so that transmit test preparation.Rinse the content of colon well and colon is put back to the abdominal cavity of animal.According to the experiment of setting, in sections, add test preparation after the 20mM sodium phosphate buffer of filling 1mL/kg pH7.4, imitate the actual colonic environment in the clinical setting more accurately.

Allow rat (n=3) to prepare the back and be exposed to every kind of test formulation forward horizontal stand 1 hour nearly in operation.Inject in the per rectum and give gabapentin-lauryl sulfate salt complex or gabapentin and transmit with 10mg gabapentin-lauryl sulfate or 10mg gabapentin/rat.Obtained blood sample and analyzed gabapentin concentration from the jugular vein conduit at 0,15,30,60,90,120,180 and 240 minute.After 4 hour testing period finished, make rat euthanasia with excessive pentobarbital.Cut off the colonic segment of every rat and vertically open along anti-Mesenteric border.The stimulation of each intestinal segment of perusal and any obviously unusual.Be put in the colon that cuts off on the scale paper and to measure proximate colon surface long-pending.The mucosa naked eyes of any test rat there is no tissue pathologies change.

Control rats (n=3) is handled with the gabapentin intravenous, and dosage is the 1mg/ rat.Analyze gabapentin concentration at the identical decimation in time blood sample of above pointing out.

The animal mean plasma concentration is shown in Table A-C in the gabapentin plasma concentration of every experimental animal and each test group.Fig. 5 is shown as the average gabapentin concentration of each test group of time function.

Table A

Gabapentin-intravenous administration
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Mean (ng/mL)	Standard deviation
0	0	0	0	0.0	0.0
						0.03	3340	2170	2330	2613.3	634.4
0.167	1420	1280	1080	1260.0	170.9
						0.5	933	868	855	885.3	41.8
1	878	867	779	841.3	54.3
						1.5	714	770	648	710.7	61.1
2	573	690	518	593.7	87.8
						3	505	558	415	492.7	72.3

Table B

Gabapentin-colon intubate
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Mean (ng/mL)	Standard deviation
0	0	0	0	0.0	0.0
						0.25	40.6	53.8	32	42.1	11.0
0.5	82.5	100	64.8	82.4	17.6
						1	189	210	83.8	160.9	67.6
1.5	266	240	78.6	194.9	101.5
						3	413	265	92.9	257.0	160.2
4	279	322	94.7	231.9	120.7

Table C

Gabapentin lauryl sulfate-colon intubate
						Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Mean (ng/mL)	Standard deviation
0	0	0	0	0.0	0.0
						0.25	2160	2380	2790	2443.3	319.7
0.5	2110	2710	4440	3086.7	1209.8
						1	2990	3280	3960	3410.0	497.9
1.5	3050	3270	33750	3356.7	358.0
						3	2170	2410	2140	2240.0	148.0
4	1380	1520	1380	1426.7	80.8

Embodiment 3

Absorb in the body

28 rats are divided into 7 test group (n=4) at random.Will by embodiment 1A describe the gabapentin of preparation or gabapentin-lauryl sulfate salt complex through intubation catheter to the rat preduodenal section start, dosage is respectively 5mg/ rat, 10mg/ rat and 20mg/ rat.Remaining test group intravenous gives 1mg/kg gabapentin.

After 4 hours, extract the blood sample of every animal and analyze gabapentin content.The result is shown in table D-H and Fig. 6 A-6C.

Table D

The gabapentin lauryl sulfate, duodenum dosage 5mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (ng/mL)	Mean	Standard deviation
0	0	0	0	0	0	0
							0.25	1490	1410	2130	2400	1857.5	484.4
0.5	2690	2080	3210	3700	2920	695.5
							1	2380	2720	2750	4640	3122.5	1025.5
1.5	2500	2620	2470	4010	2900.0	742.8
							2	1970	2740	1520	3620	2462.5	921.5
3	1580	1670	1230	2860	1835.0	709.2
							4	967	1120	696	1710	1123.25	428.8

Table E

The gabapentin lauryl sulfate, duodenum dosage 10mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (ng/mL)	Mean	Standard deviation
0	0	0	0	0	0	0
							0.25	2260	2510	2440	3080	2572.5	354.3
0.5	3210	4010	3220	4350	3697.5	574.2
							1	3670	3150	4010	4910	3935	740.0
1.5	2890	4590	4240	6370	4522.5	1433.3
							2	2310	3880	4200	5190	3895	1194.8
3	1410	3630	5210	3400	3412.5	1558.7
							4	981	2230	2430	1760	1850.2	644.0

Table F

The gabapentin lauryl sulfate, duodenum dosage 20mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (mg/mL)	Mean	Standard deviation
0	0	0	0	0	0	0
							0.25	5570	4270	5910	3420	4792.5	1156.2
0.5	5320	4680	6410	4820	5307.5	784.7
							1	7370	6610	7000	6550	6862.5	381.4
1.5	6770	6820	7830	8380	7450	789.3
							2	5670	6980	8100	9410	7540	1593.842
3	3720	5970	5880	7210	5695	1449.793
							4	2570	4980	3330	4060	3735	1029.061

Table G

Gabapentin, duodenum dosage 5mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (ng/mL)	Mean	Standard deviation
0	0	0	5.71	0	1.4275	2.855
							0.25	3920	2590	3110	4020	3410	681.8
0.5	7500	4420	4400	6850	5792.5	1618.3
							1	10800	7610	6350	7870	8157.5	1882.6
1.5	11400	8410	7260	7740	8702.5	1859.2
							2	9390	6800	9370	6670	8057.5	1528.0
3	6350	5830	5640	5370	5797.5	413.9
							4	4710	3490	3900	3350	3862.5	611.3

Table H

Gabapentin, duodenum dosage 10mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (ng/mL)	Mean	Standard deviation
0	0	0	5.62	0	1.405	2.81
							0.25	5690	2760	5740	5110	4825	1406.1
0.5	7560	4480	6490	9260	7447.5	2096.9
							1	7600	7320	Disappearance	11400	8773.333	2279.1
1.5	7150	6170	10500	14900	9680	3943.0
							2	8020	11000	12500	14800	11580	2841.6
3	6580	12900	9740	14100	10830	3377.8
							4	4610	12400	6820	8660	8122.5	3297.5

Table I

Gabapentin, duodenum dosage 20mg/ rat
							Time (h)	Rat 1 (ng/mL)	Rat 2 (ng/mL)	Rat 3 (ng/mL)	Rat 4 (ng/mL)	Mean (ng/mL)	Standard deviation
0	0	0	0	0	0	0
							0.25	5560	6720	7910	8050	7060	1164.5
0.5	7360	9850	13100	11800	10527.5	2498.6
							1	7970	13500	13700	15800	12742.5	3347.4
1.5	10300	13400	13500	16200	13350	2411.8
							2	9530	12500	14100	17600	13432.5	3362.2
3	6530	9070	10200	16900	10675	4424.7
							4	4370	5900	6050	13900	7555	4297.6

Embodiment 4

Adopt the interior colon of body of the colon models of rat flushing ligation to absorb

Adopting known usually is the animal model of " model of colonic ligation ".With the 0.3-0.5kg Sprague-Dawley male rat after fasting anesthesia and separate sections near colon.The Excreta raw material of flushing colon.With the two ends ligation of this colon sections, simultaneously conduit is placed in the chamber and takes out in the abdomen and place on the skin so that transmit test preparation.Rinse the content of colon well and colon is put back to the abdominal cavity of animal.According to the experiment of setting, in sections, add test preparation after the 20mM sodium phosphate buffer of filling 1mL/kg pH7.4, imitate the actual colonic environment in the clinical setting more accurately.

Allow rat (n=3) to prepare the back and be exposed to every kind of test formulation forward horizontal stand 1 hour nearly in operation.Inject in the per rectum and give pregabalin-lauryl sulfate salt complex or pregabalin and with 10mg pregabalin/rat administration.Obtained blood sample and analyzed pregabalin concentration from the jugular vein conduit at 0,15,30,60,90,120,180 and 240 minute.After 4 hour testing period finished, make rat euthanasia with excessive pentobarbital.Cut off the colonic segment of every rat and vertically open along anti-Mesenteric border.The stimulation of each intestinal segment of perusal and any obviously unusual.Be put in the colon that cuts off on the scale paper and to measure proximate colon surface long-pending.

Control rats (n=3) is handled with the pregabalin intravenous, and dosage is the 1mg/ rat.The identical decimation in time blood sample of above pointing out.

Embodiment 5

Absorb in the body

28 rats are divided into 7 test groups (n=4) at random.Will by embodiment 1B describe the pregabalin of preparation or pregabalin-lauryl sulfate salt complex through intubation catheter to the rat preduodenal section start, dosage is respectively 5mg/ rat, 10mg/ rat and 20mg/ rat.Remaining test group intravenous gives 1mg/kg pregabalin.

After date extracts the blood sample of every animal and analyzes pregabalin content during through 4 hours.Determine dosage, AUC and bioavailability with being similar to the computing method that embodiment 3 is used for gabapentin.

Embodiment 6

Preparation contains the dosage form of medicine-transhipment part complex

A. gabapentin-transhipment part complex

Be prepared as follows device shown in Figure 7.The compositions that forms compartment is mixed, and said composition comprises percetage by weight 92.25% gabapentin-transhipment part complex, 5% carboxypolymethylene potassium, about 5,000,000 the poly(ethylene oxide) of 2% molecular weight and 0.5% silicon dioxide.Then, make mixture pass through 40 order stainless steel sifts, dry type is mixed 30 minutes generation homogeneous mixtures in the V-blender then.Then, make 0.25% magnesium stearate by 80 order stainless steel sifts, and additional mixing 5 to 8 minutes.Then, the powder of even dry mixed is put into funnel and be supplied to compartment shaping press, and the mixture of known quantity is compressed to being designed for 5/8 inch oral oval outward appearance.Then at Accela-Cota ^Use the wall forming composition with the pre-compartment of ellipse (precompartments) coating (coated) in the wall shaping coating machine, said composition contains 91% cellulose acetate (containing 39.8% acetyl group) and 9% Polyethylene Glycol 3350.After the coating, the drug compartment of wall coating is removed and is transferred to the drying baker to remove the residual organic solvent that uses in the wall forming process from coating machine.Then, plater is transferred in 50 ℃ of air dry ovens dry about 12 hours.Then, on the wall of device, form one or more outlets with laser.

B. pregabalin-transhipment part complex

Be prepared as follows device shown in Figure 7.The compositions that forms compartment is mixed, and said composition comprises percetage by weight 92.25% pregabalin-transhipment part complex, 5% carboxypolymethylene potassium, about 5,000,000 the poly(ethylene oxide) of 2% molecular weight and 0.5% silicon dioxide.Then, make mixture pass through 40 order stainless steel sifts, dry type is mixed 30 minutes generation homogeneous mixtures in the V-blender then.Then, make 0.25% magnesium stearate by 80 order stainless steel sifts, and additional mixing 5 to 8 minutes.Then, the powder of even dry mixed is put into funnel and be supplied to compartment shaping press, and the mixture of known quantity is compressed to being designed for 5/8 inch oral oval outward appearance.Then at Accela-Cota ^Use the wall forming composition with the pre-compartment of ellipse (precompartments) coating (coated) in the wall shaping coating machine, said composition contains 91% cellulose acetate (containing 39.8% acetyl group) and 9% Polyethylene Glycol 3350.After the coating, the drug compartment of wall coating is removed and is transferred to the drying baker to remove the residual organic solvent that uses in the wall forming process from coating machine.Then, plater is transferred in 50 ℃ of air dry ovens dry about 12 hours.Then, on the wall of device, form one or more outlets with laser.

Embodiment 7

Preparation contains the dosage form of gabapentin-transhipment part complex

Be prepared as follows the dosage form that contains gabapentin layer and gabapentin-lauryl sulfate complex layer, as shown in Figure 9.

With the polyvinylpyrrolidone of the poly(ethylene oxide) of 10g gabapentin, 1.18g molecular weight 100,000 and 0.53g molecular weight about 38,000 in conventional mixer dry mixed 20 minutes to produce homogeneous mixture.Then, follow blender to continue to stir down, 4mL degeneration dehydrated alcohol is slowly added in the drying composite of 3 kinds of components.Continue again to mix 5 to 8 minutes.Blended wet compositions is spent the night by 16 mesh sieves and in drying at room temperature.Then, make dried granules pass through 16 mesh sieves and add the 0.06g magnesium stearate and all the components dry mixed 5 minutes.Fresh pellet prepares to be used for preparing the initial dose layer of dosage form.

Be prepared as follows and contain gabapentin-lauryl sulfate complex layer in the dosage form.At first, 9.30g is pressed gabapentin-lauryl sulfate salt complex, the 0.50g molecular weight 5 that embodiment 1A describes preparation, the polyvinylpyrrolidone of 000,000 poly(ethylene oxide), 0.10g molecular weight about 38,000 in conventional mixer dry mixed 20 minutes to produce homogeneous mixture.Then, the degeneration dehydrated alcohol is slowly added in the mixture, continue to mix 5 minutes.Blended wet compositions is spent the night by 16 mesh sieves and in drying at room temperature.Then, make dried granules pass through 16 mesh sieves and add the 0.10g magnesium stearate and all dry ingredient dry mixed 5 minutes.

Be prepared as follows the promoting layer that contains the osmopolymer hydrogel composition.At first, make pharmaceutically acceptable poly(ethylene oxide), the 5g Carbopol of 58.67g molecular weight 7,000,000 ^974P, 30g sodium chloride and 1g ferrum oxide sieve by 40 mesh sieves respectively.The hydroxypropyl emthylcellulose of composition that sieves and 5g molecular weight 9,200 mixes the generation homogeneous mixture.Then, 50mL degeneration dehydrated alcohol is slowly added mixture and continuation mixing 5 minutes.Then, add 0.080g butylated hydroxytoluene and continuation mixing.The granule that makes prepared fresh is by 20 mesh sieves and dry 20 hours of room temperature (ambient temperature).Make exsiccant composition by 20 mesh sieves and add the 0.25g magnesium stearate and all the components was mixed 5 minutes.

Be prepared as follows 3 layers of dosage form.At first, 118mg gabapentin compositions is added stamping machine and die device and make firm by ramming, then will 511mg gabapentin-lauryl sulfate salt composite add in the mould as the second layer and make firm by ramming once more.Then, adding 315mg hydrogel composition also is compacted in the die set of 9/32 inch (0.714cm) diameter 3 layers under 1 ton of (1000kg) compression stress, forms 3 layers of core (tablet) closely.

It is that the semi-permeable wall forming composition of poly(ethylene oxide)-polyoxy third rare copolymer of 7680-9510 is by making composition with 80 that preparation contains 80.0wt% cellulose acetate (containing 39.8% acetyl base unit weight) and 20.0% molecular weight: the 20wt/wt compositions is dissolved in acetone to produce 5.0% solid solution.The wall forming composition is sprayed on 3 layers the core or, produces 60 to 80mg thick semi-permeable wall on every side.

Then, the outlet of boring 40mil (1.02mm) with laser in 3 synusia agent of semi-permeable wall makes the gabapentin layer contact with the outside of releasing device.Make the dosage form drying to remove any residual solvent and water.

Embodiment 8

The dissolution in vitro that contains the dosage form of gabapentin-transhipment part complex

In 37 ℃ of waters bath with thermostatic control,, dosage form determines to press the dissolution in vitro rate that embodiment 4 and 5 describes the dosage form of preparation in the sample fixer that connects the wire coil on the USP Type VII body lotion analyzer (bath indexer) by being positioned over.The aliquot of release medium is injected chromatographic system be released into the amount that medium stimulates the gabapentin (or pregabalin) of simulated gastric fluid (AGF) to determine each test interval.

Embodiment 9

Preparation contains the dosage form of gabapentin-transhipment part complex

Be prepared as follows the dosage form that Figure 10 A-10C represents.Be prepared as follows and prolong the unit dose that discharges gabapentin-lauryl sulfate salt complex.Make the classifying screen of the gabapentin of 200g gabapentin-lauryl sulfate complex form by per inch 40 silk screens.Make 25g number-average molecular weight 9, the hydroxypropyl emthylcellulose of 200g/ mole and 15g molecular weight 242, the hydroxypropyl emthylcellulose that 000g is every mole sieves by the classifying screen (sizing screen) of per inch 40 silk screens.The average methoxy base unit weight of the average hydroxyl amount of every kind of each self-contained 8 percetage by weight of cellulose and 22 percetages by weight.Fractionated powder is rolled to be mixed 5 minutes.Add while stirring dehydrated alcohol to mixture until forming moist agglomerate.Make the classifying screen of wet agglomerate by per inch 20 silk screens.The moist pellet that generates spends the night at air drying, and then by 20 mesh sieves.Make the lubricant of 2g tabletting, the classifying screen that magnesium stearate is passed through per inch 80 silk screens.Fractionated magnesium stearate is mixed the last granule of formation with dried granules.

It is in 0.281 inch the die cavity that the particulate fraction that 733mg is last is put in internal diameter.Under 1 ton of head, dash the tablet that this part is compressed the vertical capsule outward appearance of formation with dark concave surface.

Capsule be conveyed into Tait Capsealer Machine (Tait Design and MachineCo., Manheim, Pa.) in, each capsule is printed on 3 bands therein.The material that forms band is 50wt% ethylcellulose dispersion (Surelease ^, Colorcon, West Point is Pa.) with 50wt% ethyl acrylate methylmethacrylate (Eudragit ^NE 30D, RohmPharma, Weiterstadt, Germany).Band is suitable for to aqueous dispersion and distillates superfluous water when warm air occurring.The diameter of band is 2 millimeters.

Though describe and point out the features and advantages of the present invention with existing embodiment, the technical staff of pharmaceutical field can not break away from purport of the present invention with understanding and the method that description is described is carried out multiple modification, change, interpolation and omission.

Claims (24)

1. one kind contains gabapentin or pregabalin and transhipment material partly, and described gabapentin or pregabalin and described transhipment partly form complex.

2. the material of claim 1, wherein said transhipment partly is the alkyl sulfate that contains 6-12 carbon atom.

3. the material of claim 2, wherein said alkyl sulfate is a lauryl sulfate.

4. compositions, it comprises,

The complex of partly forming by gabapentin or pregabalin and transhipment and

Pharmaceutically acceptable vehicle,

Wherein said compositions infra gastrointestinal is absorbed as gabapentin or pregabalin at least 5 times.

5. the compositions of claim 4, wherein said transhipment partly is the alkyl sulfate that contains 6-12 carbon atom.

6. the compositions of claim 5, wherein said alkyl sulfate is a lauryl sulfate.

7. dosage form, it comprises the compositions of claim 4.

8. dosage form, it comprises the material of claim 1.

9. the dosage form of claim 8, wherein this dosage form is an osmotic dosage form.

10. the dosage form of claim 9, it comprises with the lower part: (i) promoting layer; The medicine layer that (ii) contains gabapentin-transhipment part complex or pregabalin-transhipment part complex; (iii) center on the semi-permeable wall that promoting layer and medicine layer provide; (iv) outlet.

11. the dosage form of claim 9, it comprises with the lower part: (i) around permeating the semi-permeable wall that preparation gabapentin-transhipment part complex or pregabalin-transhipment part complex, penetrating agent and osmopolymer provide; (ii) outlet.

12. the dosage form of claim 9, wherein this dosage form provides the total daily dose between the 200-3600mg.

13. comprising, an improvement that contains the dosage form of gabapentin or pregabalin, described improvement contain the partly dosage form by the associating complex of tight ion pair key of gabapentin or pregabalin and transhipment.

14. the improvement dosage form of claim 13, wherein said transhipment partly are the alkyl sulfates that contains 6-12 carbon atom.

15. the improvement dosage form of claim 14, wherein said alkyl sulfate is a lauryl sulfate.

16. a method that gives gabapentin or pregabalin, this method comprises:

The material of claim 1 there is the patient who needs.

17. the method for claim 16, wherein said is that oral administration gives.

18. a method for preparing the complex of gabapentin or pregabalin and transhipment part, this method comprises

Gabapentin or pregabalin are provided;

The transhipment part is provided;

Gabapentin or pregabalin and transhipment part in being lower than the solvent of dielectric constant of water, dielectric constant is combined;

Thereby described combination causes the formation of the complex of gabapentin or pregabalin and transhipment part.

19. the method for claim 18, wherein said combination comprises that (i) makes gabapentin or pregabalin combine in aqueous solvent with the transhipment part, the described solvent that (ii) dielectric constant is lower than the dielectric constant of water joins in the described aqueous solvent and (iii) reclaim described complex from described solvent.

20. the method for claim 18, wherein said combination are included in dielectric constant and contact in 1/2nd the solvent less than the dielectric constant of water at least.

21. the method for claim 20, wherein said solvent is selected from methanol, ethanol, acetone, benzene, dichloromethane and carbon tetrachloride.

22. a method of improving the gastrointestinal absorption of gabapentin or pregabalin, this method comprises

The complex that contains gabapentin or pregabalin and transhipment part is provided; With

Give the patient with this complex.

23. the method for claim 22, the absorption of wherein said improvement comprise that the lower gastrointestinal tract of improvement absorbs.

24. the method for claim 22, the absorption of wherein said improvement comprise that the upper gastrointestinal of improvement absorbs.

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