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

Compositions and dosage forms for enhancing absorption of gabapentin and pregabalin

Background of the invention

The present invention relates to compositions and dosage forms for the delivery of gabapentin or pregabalin. In more detail, the present invention relates to a complex of gabapentin or pregabalin and a transport moiety, wherein the complex facilitates the absorption of the drug in the gastrointestinal tract and more particularly in the lower gastrointestinal tract.

Background of the invention

Scientific understanding of the pathogenesis of neuropathic pain has developed over the past decade, and basic research in animal models of neuropathic pain and human clinical trials have revealed pathophysiological and biochemical changes in the nervous system due to injury or disease (Backonja, MM, Clin. J. Pain, 16 (2):S67-72 (2000)). Neuropathic pain is a chronic condition that often occurs in cancer patients, stroke victims, the elderly, people with diabetes (eg, painful diabetic neuropathy), patients with herpes zoster (shingles) (eg, postherpetic neuralgia), and neuropathic pain Patients with degenerative diseases (such as amyotrophic lateral sclerosis (ALS)). Clinical features of neuropathic pain include burning sensations, spontaneous pains, flashing pains, and evoked pains. Different pathophysiological mechanisms cause specific sensory symptoms, such as dynamic mechanical allodynia and cold hyperalgesia.

Treatment of neuropathic pain includes the use of conventional analgesics such as NSAIDs, analgesics, opiates, or tricyclic antidepressants (Max, MB, Ann. Neurol., 35 (Suppl): S50- S53 (1994); Raja, SN et al. Neurology 59 :1015 (2002); Galer, BS et al. Pain 80 :533 (1999)). These drugs and other therapies are not accepted by many patients because they do not provide adequate pain relief or have intolerable side effects.

The anticonvulsant gabapentin has been shown to have significant analgesic effects in the treatment of neuropathic pain (and in particular painful diabetic neuropathy and postherpetic neuralgia) (Wheeler, G., Curr. Opin. Invest, Drugs, 3 (3 ): 470 (2002)). Gabapentin is also an effective drug for the control of some types of seizures, especially those induced by epilepsy (Johannessen, SI et al., Ther. Drug Monitoring, 25 :347 (2003)). Similarly, pregabalin has been shown to be effective in the treatment of postherpetic neuralgia and painful diabetic neuropathy (Dworkin, RH et al., Neurology, 60 :1274 (2003)).

Gabapentin is absorbed from the proximal small intestine into the bloodstream via the L-amino acid transport system (Johannessen, supra at p. 350). The bioavailability of drugs is dose-dependent, apparently because the L-amino acid transport system saturates, limiting the amount of drug absorbed (Stewart, BH et al., Pharm. Res., 10 :276 (1993)). For example, serum gabapentin concentrations increased linearly with dose up to approximately 1800 mg/day and then continued to increase at higher but lower than expected doses, possibly because the mechanism of absorption from the upper gastrointestinal tract became saturated (Stewart, supra ( supra.)).

The L-amino transport system responsible for the absorption of gabapentin is mainly present in the epithelial cells of the small intestine (Kanai, YJ et al., J. Toxicol. Sci., 28 (1):1 (2003)), thereby limiting drug absorption. Pregabalin has also been shown to be absorbed via the L-amino transport system and other amino acid transport systems ((Dworkin, supra, p. 1282).

Differences in the cellular characteristics of the upper and lower GI tracts also contribute to underabsorption of molecules from the lower GI tract. Figure 1 illustrates the two general pathways for transporting compounds across the gastrointestinal epithelium. Individual epithelial cells, represented by 10a, 10b, 10c, form a cellular barrier along the small and large intestines. Individual cells are separated by water channels or tight junctions (eg 12a, 12b). Transport across the epithelium can be via either transcellular or paracellular pathways or both. Transcellular channels of transport (arrow 14 in Figure 1) refer to the movement of compounds across epithelial cell walls and cell bodies by passive diffusion or carrier-mediated transport. Paracellular channels of transport refer to the movement of molecules through tight junctions between individual cells, as indicated by arrows 16 . Paracellular channels are less specific but have a much greater overall capacity, in part because they are present throughout the GI tract. However, tight junctions are distributed differently along the GI tract, with an increasing trend in the effective "tightness" of tight junctions from proximal to distal. Thus, the duodenum of the upper GI tract is more "leaky" than the ileum of the upper GI tract, and the ileum is more "leaky" than the colon of the lower GI tract (Knauf, H. et al., Klin. Wochenschr., 60 (19): 1191-1200 (1982)).

Since the usual residence time of a drug in the upper gastrointestinal tract is from about 4 to 6 hours, a poorly colonically absorbed drug is absorbed through the body only for a period of 4 to 6 hours after oral ingestion. It is generally medically desirable that a given drug appear in a patient's bloodstream at a relatively constant concentration throughout the day. To achieve this with conventional drug formulations that exhibit minimal colonic absorption, the patient will need to take the drug 3 to 4 times a day. This kind of inconvenient practical experience for patients is not the best treatment plan. Therefore, there is a need to obtain such drugs that are absorbed long-term throughout the day and administered once a day.

In order to provide a constant dose of therapy, conventional drug development has proposed various controlled release drug systems. Such systems function by releasing their drug payload over an extended period of time after administration. However, these conventional forms of controlled release systems are ineffective in situations where colonic absorption of the drug is minimal. Since the drug is only absorbed in the upper GI tract and since the residence time of the drug in the upper GI tract is only 4 to 6 hours, the fact that the proposed controlled-release dosage form can still release its payload after the dosage form residence time in the upper GI tract is not true. It means that the body will continue to absorb the controlled release drug after staying in the upper gastrointestinal tract for 4 to 6 hours. In contrast, drugs released from controlled release dosage forms after the dosage form has entered the lower GI tract are generally not absorbed, but are excreted from the body with other materials in the lower GI tract.

The usefulness of gabapentin to control seizures or neuropathic pain would be greatly improved if gabapentin were present in the patient's bloodstream at drug-effective concentrations throughout the day. To achieve this when using conventional gabapentin formulations, the patient will need to ingest gabapentin doses 3 to 4 times per day. Practical experience with this patient inconvenience suggests that it is not an optimal treatment option. Furthermore, a true once-a-day regimen of gabapentin would provide advantages that outweigh convenience. The relatively constant dose of gabapentin in the patient's bloodstream offers many other advantages. Therefore, there is a need for once-daily dosing of gabapentin for long-term absorption throughout the day.

Invention Overview

Thus, in one aspect the invention includes substances comprising gabapentin or pregabalin and a transport moiety, complexes of gabapentin or pregabalin and a transport moiety.

In one embodiment, the transport moiety is an alkyl sulfate having 6-12 carbon atoms. A preferred alkyl sulfate is lauryl sulfate.

In another aspect, the present invention includes a composition comprising a complex of gabapentin or pregabalin and a transport moiety and a pharmaceutically acceptable carrier, wherein the absorption of the composition in the lower gastrointestinal tract is at least that of gabapentin or pregabalin. 5 times.

In another aspect, the invention includes an embodiment of a dosage form comprising a composition as described above or a substance as described above.

In one embodiment, the dosage form is an osmotic dosage form. In one embodiment, an exemplary dosage form has (i) a push layer; (ii) a drug layer comprising a gabapentin-transport moiety complex or a pregabalin-transport moiety complex; (iii) a surrounding push layer and drug layer The semi-permeable wall; and (iv) the outlet. Another exemplary dosage form has (i) a semipermeable wall surrounding the osmotic agent gabapentin-transport moiety complex or pregabalin-transport moiety complex, the osmolyte, and the osmopolymer; and (ii) an outlet.

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

In another aspect, the present invention provides improved dosage forms comprising gabapentin or pregabalin. The improvement includes dosage forms comprising a complex of gabapentin or pregabalin and a transport moiety associated in a tight ion-pair bond.

In another aspect, the present invention includes methods of administering gabapentin or pregabalin, comprising substances described above, to a patient in need thereof.

In one embodiment, the substance is administered orally.

In another aspect, the present invention includes a method for preparing a complex of gabapentin or pregabalin and a transport moiety, comprising providing gabapentin or pregabalin; providing the transport moiety; and making gabapentin or pregabalin and the transport moiety at a dielectric constant below combination in a solvent of water; whereby said combination forms a complex of gabapentin or pregabalin and the transport moiety.

In one embodiment, conjugating comprises (i) conjugating gabapentin or pregabalin and the transport moiety in an aqueous solvent, (ii) adding a solvent with a lower dielectric constant than water to the aqueous solvent, and (iii) extracting The complex is recovered from the solvent.

In another embodiment, binding comprises contacting in a solvent having a dielectric constant that is at least one-half that of water. Exemplary solvents include methanol, ethanol, acetone, benzene, methylene chloride, and carbon tetrachloride.

In another aspect, the invention includes a method of improving gastrointestinal absorption of gabapentin or pregabalin comprising providing a complex comprising gabapentin or pregabalin and a transport moiety, the complex being characterized by a tight ion-pair bond; and The complex is administered to a patient.

In one embodiment, improved absorption includes improved absorption from the lower gastrointestinal tract.

In another embodiment, improved absorption comprises improved absorption from the upper gastrointestinal tract.

These aspects, as well as other aspects, features and advantages of the present invention, will become more apparent from the following detailed disclosure of the invention and appended claims.

Brief description of attached drawings

The following drawings are not drawn to scale, but are presented to illustrate the different aspects of the present invention

implementation plan.

Figure 1 is a schematic diagram of a gastrointestinal epithelial cell illustrating transcellular and paracellular pathways for transport molecules through the epithelium;

Figure 2A shows the chemical structure of gabapentin;

Figure 2B shows the chemical structure of pregabalin;

Figure 3A shows a general synthetic reaction scheme for the preparation of gabapentin-transport moiety or pregabalin-transport moiety complexes;

Figure 3B shows a general synthetic reaction scheme for the preparation of gabapentin-transport moiety or pregabalin-transport moiety complexes, wherein the transport moiety includes a sulfate group;

Fig. 3 C represents the synthetic reaction process of preparing gabapentin-alkyl sulfate complex;

Figure 3D represents the synthetic reaction process for preparing pregabalin-alkyl sulfate complex;

Figures 4A-4D are gabapentin (Figure 4A), sodium lauryl sulfate (Figure 4B), a physical mixture of gabapentin and sodium lauryl sulfate (loose ion pair) (Figure 4C), and a gabapentin-lauryl sulfate complex (Figure 4B). 4D) FTIR scan;

Figure 5 shows gabapentin administered intravenously (triangles) and cannulated into the colon (circles) and gabapentin lauryl sulfate complex (diamonds) into the ligated colon as time (in hours) Indicates the gabapentin plasma concentration (ng/mL) in the rat of ) function;

Figure 6A shows gabapentin administered intravenously (triangles) and in the duodenum at doses of 5 mg (circles), 10 mg (squares) and 20 mg (diamonds) as a function of time (in hours) in rats Gabapentin plasma concentration in (ng/mL);

Figure 6B shows gabapentin lauryl sulfate complex administered intravenously (triangles) and administered to the duodenum at doses of 5 mg (circles), 10 mg (squares) and 20 mg (diamonds) as time (in Gabapentin plasma concentration (ng/mL) in rats as a function of hours (expressed in hours);

Figure 6C is a graph of gabapentin bioavailability (%) as a function of dose after administration of gabapentin (inverted triangle) or gabapentin lauryl sulfate complex (circle) to the duodenum of rats;

Figure 7 illustrates an exemplary osmotic dosage form shown in cross-sectional view;

Figure 8 illustrates another exemplary osmotic dosage form for a once-daily dose of gabapentin comprising a gabapentin-transport moiety complex or pregabalin-transport moiety complex, and an optional loading dose in the outer coating complexes;

Figure 9 illustrates one embodiment of a once-a-day gabapentin (or pregabalin) dosage form containing both gabapentin (or pregabalin) and a gabapentin (or pregabalin)-transport moiety complex, and the coating optionally A loading dose of gabapentin (or pregabalin);

Figures 10A-10C illustrate administration or pre-dose embodiments where the complex of the gabapentin (or pregabalin)-transporter moiety complex is contained in a matrix (Figure 10A), administered after ingestion into the gastrointestinal tract ( FIG. 10B ) and after sufficient erosion of the matrix has caused the strip-like portion of the device to separate ( FIG. 10C ).

Details

I. Definition

The present invention is best understood by reference to the following definitions, drawings and exemplary notices provided herein.

By "composition" is meant one or more gabapentin-transport moiety or pregabalin-transport moiety complexes, optionally in combination with additional active pharmaceutical ingredients, and/or optionally in combination with inactive ingredients (e.g. pharmaceutical Acceptable carriers, excipients, suspending agents, surfactants, disintegrants, binders, diluents, lubricants, stabilizers, antioxidants, penetrants, colorants, plasticizers, etc.) in combination.

By "complex" is meant a substance comprising a drug moiety and a transport moiety associated by tight ion-pair bonds. Drug-moiety-transporter complexes can be distinguished from loose ion-pairs of drug and transporter moieties by differences in partition behavior in octanol/water, with the following characteristic relationship;

ΔLogD=LogD(complex)-LogD(loose ion pair) ≥ 0.15 (equation 1) where, D, the partition coefficient (apparent partition coefficient), is at a set pH (usually about pH=5.0 to about pH=7.0 ) and the ratio of the equilibrium concentrations of all species drug moieties and transport moieties in octanol to the same species in water (deionized water) at 25°C. LogD(complex) was used to determine the complex of the drug moiety and the transport moiety prepared as indicated herein. LogD (loose ion pair) was used to determine the physical mixture of the drug moiety and the transport moiety in deionized water. For example, the octanol/water apparent partition coefficient (D=C _octanol /C _water ) of a putative complex (25°C in deionized water) can be determined and compared to 1: 1 (mol/mol) physical mixture comparison. A putative complex is confirmed if it is determined that the difference between the Log D of the putative complex (D+T-) and the Log D of the 1:1 (mol/mol) physical mixture (D ⁺ ∥T ^- ) is greater than or equal to 0.15 Compounds are complexes according to the invention. In a preferred embodiment, ΔLog D > 0.20, and more preferably ΔLog D > 0.25, and still more preferably ΔLog D > 0.35.

Dosage form"means a pharmaceutical composition in a vehicle, carrier, vehicle or device suitable for administration to a patient in need thereof.

"Drug" or "drug moiety" refers to a drug, compound or agent, or a residue of such a drug, compound or agent, that provides some pharmacological effect when administered to a patient. Suitable for use in complex formation, the drug comprises an acidic, basic or zwitterionic structural element, or an acidic, basic or zwitterionic residue structural element.

"Fatty acid" refers to any organic acid group of general formula CH ₃ (C _n H _x )COOH, wherein the hydrocarbon chain is saturated (x = 2n, such as palmitic acid, C ₁₅ H ₃₁ COOH) or unsaturated (x =2n-2, such as oleic acid, CH ₃ C ₁₆ H ₃₀ COOH).

"Gabapentin" refers to 1-( _aminomethyl )cyclohexaneacetic acid having a molecular formula of _C9H17NO2 and _a molecular weight of 171.24. It is commercially available under the trade name Neurontin ^(R) . Its structure is shown in Figure 2A.

By "gut" or "gastrointestinal tract" is meant the portion of the alimentary canal that extends from the lower opening of the stomach to the anus and includes the small intestine (duodenum, jejunum, and ileum) and large intestine (ascending colon, transverse colon, descending colon, sigmoid colon and rectum).

"Loose ion pair" refers to a pair of ions that, at physiological pH and in an aqueous environment, are readily inter-exchangeable with other loosely paired or free ions that may be present in the loose ion pair environment. Using isotopic labeling and NMR or mass spectrometry, loose ion pairs can be found experimentally by recording the exchange of a member of a loose ion pair with another ion at physiological pH and in an aqueous environment. Reverse-phase HPLC can also be used to find loose ion pairs experimentally by recording their separation at physiological pH and in an aqueous environment. Loose ion pairs may also be referred to as "physical mixtures" and are formed by physically mixing ion pairs together in a medium.

By "lower gastrointestinal tract" or "lower G.I. tract" is meant the large intestine.

By "patient" is meant an animal, preferably a mammal, more preferably a human, in need of therapeutic intervention.

"Tight ion pair" refers to an ion pair that, at physiological pH and in an aqueous environment, is not readily interchangeable with other loose free ion pairs that may exist in a tight ion pair environment. Tight ion pairs can be detected experimentally by using isotope labeling and NMR or mass spectrometry to record that one ion of a tight ion pair does not exchange with the other at physiological pH and in an aqueous environment. Tight ion pairs can be found experimentally, ie, by using reversed-phase HPLC to document the lack of ion pair separation at physiological pH and in an aqueous environment.

"Transport moiety" means a compound capable of forming a complex with a drug, or a residue of a compound that has formed a complex with a drug, wherein the transport moiety improves the transport of the drug across epithelial tissue compared to the transport of the uncomplexed drug . The transport moiety comprises a hydrophobic portion and an acidic, basic or zwitterionic moiety or an acidic, basic or zwitterionic residue moiety. In a preferred embodiment, the hydrophobic moiety comprises hydrocarbon chains. In one embodiment, the basic moiety or basic residue moiety has a pKa of greater than about 7.0, preferably greater than about 8.0.

"Pharmaceutical composition" means a composition suitable for administration to a patient in need thereof.

Pregabalin refers to (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid). Pregabalin may also be referred to as (S)-3-isobutyl GABA or CI-1008 in the literature. The structure of pregabalin is shown in Figure 2B.

"Structural component" refers to (i) a chemical group that is part of a macromolecule, and (ii) a chemical group that has a discernible chemical functionality. For example, an acidic group or a basic group on a compound is a structural component.

"Substance" refers to a chemical entity having specific characteristics.

"Residue structural moiety" refers to a structural moiety that is modified by an interaction or reaction with another compound, chemical group, ion, atom, or the like. For example, the carboxyl moiety (COOH) interacts with sodium to form the sodium carboxylate salt, and COO- is the residue moiety.

"Upper gastrointestinal tract" or "upper G.I. tract" refers to the portion of the gastrointestinal tract that includes the stomach and small intestine.

II. Complex formation and identification

As noted above, gabapentin is effective in anticonvulsant and neuropathic pain relief. Gabapentin shown in Figure 2A is a zwitterionic compound with a pKa ₁ of 3.7 and a pKa ₂ of 10.7. It is easily soluble in water and alkaline and acidic aqueous solutions. The logarithm of the partition coefficient (n-octanol/0.05M phosphate buffer) at pH 7.4 was -1.25. These properties, together with the fact that it is adsorbed by the L-amino acid transport system discussed above, lead to poor absorption of this compound in the gastrointestinal tract. A pH gradient in the GI tract from a pH of about 1.2 in the stomach to a pH of about 7.5 in the distal ileum and large intestine (Evans, DF et al., Gut, 29 : 1035-1041 (1988)) implies a range of pH across the GI tract. Gabapentin is charged, which also makes it less absorbed. Pregabalin, shown in Figure 2B, is a structural analog of gabapentin and is affected by the same characteristics, resulting in less absorption in the lower gastrointestinal tract.

Thus, in one aspect the present invention provides compounds comprising gabapentin or pregabalin which significantly improve absorption from the lower gastrointestinal tract. The compound is a complex of gabapentin and a transport moiety or a complex of pregabalin and a transport moiety. According to the general synthetic reaction scheme shown in Figure 3A, the compound can be prepared from a salt of a drug such as gabapentin hydrochloride or pregabalin hydrochloride. Briefly, the salt form of the drug represented by D+X- in Figure 3A is bound to the transport moiety represented by T ^- M ⁺ in the figure. Exemplary transport moieties are listed above and include fatty acids, fatty acid salts, alkyl sulfates, benzenesulfonic acid, benzoic acid, fumaric acid, and salicylic acid. These two species are combined in water to form a loose ion pair (indicated by D+∥X- in the figure) and then solvated in a solvent with a lower dielectric constant than water as will be discussed below. This approach results in the formation of a gabapentin-transporter moiety complex or a pregabalin-transporter moiety complex, where the species in the complex are associated in tight ion-pair bonds, as represented by D+T- in Figure 3A.

Figure 3B illustrates a more specific synthetic reaction scheme to form the gabapentin (or pregabalin)-transport moiety complex. In this scheme, the transport moiety is represented as the salt of the alkyl sulfate, (R-SO ₄ )-(Y) ⁺ . Alkyl sulfate and drug salt mix in water to form a loose ion pair, represented by D+∥[(R- _SO4 )]- in Figure 3B. An organic solvent with a lower dielectric constant than water is added to an aqueous solution of loose ion pairs and extracts a drug-transport moiety complex, where the drug and transport moiety are associated by a tight ion-pair bond, represented by D+[(R-SO ₄ )] - representation.

Example 1A provides a specific example of the step of preparing a gabapentin-transport moiety complex, wherein the transport moiety is an alkyl sulfate and more specifically an alkyl sulfate, as shown in Figure 3C. For example, the salt form of gabapentin, gabapentin hydrochloride, is prepared by combining gabapentin with hydrochloric acid. It is understood that other salts of gabapentin may be formed. Then, an alkyl sulfate such as lauryl sulfate is added. In Example 1A, although the sodium salt of lauryl sulfate was used, other salts are suitable, such as potassium or magnesium alkyl sulfates. Gabapentin hydrochloride binds to sodium lauryl sulfate to form an ion pair of gabapentin and lauryl sulfate, such as the loose ion pair between the species represented in Figure 3C. A solvent with a lower dielectric constant than water was added to the solution containing gabapentin and lauryl sulfate and mixed well and allowed to settle. The gabapentin lauryl sulfate complex is extracted from the solvent phase (non-aqueous phase), and the solvent is typically removed by appropriate techniques including, but not limited to, evaporation, distillation, and the like.

In Example 1A, an alkyl sulfate (lauryl sulfate) was used as an exemplary transport moiety to form a complex. It should be understood that lauryl sulfate is exemplary only and that the preparation procedure is equally applicable to other species suitable as transport moieties as well as to alkyl sulfates and fatty acids of any carbon chain length. For example, forming complexes of gabapentin (or pregabalin) with different alkyl sulfates or fatty acids or their salts, wherein the alkyl chains in the alkyl sulfates or fatty acids contain from 6 to 18 carbon atoms, more preferably 8 to 16 carbon atoms and even more preferably 10 to 14 carbon atoms. Alkyl chains may be saturated or unsaturated. Exemplary saturated alkyl chains in fatty acids contemplated for preparing complexes include butyric acid (butyric acid, 4C); valeric acid (valerenic acid, 5C); caproic acid (caproic acid, 6C); caprylic acid (caprylic acid, 8C); Nonanoic acid (nonanoic acid, 9C); capric acid (capric acid, 10C); dodecanoic acid (lauric acid, 12C); myristic acid (myristic acid, 14C); palmitic acid (palmitic acid, 16C); Acid (heptadecanoic acid, 17C) and octadecanoic acid (stearic acid, 18C), where the parentheses after the system name are the common name and the number of carbon atoms in the fatty acid. Unsaturated fatty acids include oleic acid, linoleic acid, and linolenic acid, all acids having 18 carbon atoms. Linoleic acid and linolenic acid are polyunsaturated acids. Exemplary gabapentin complexes include gabapentin palmitate, gabapentin oleate, gabapentin decanoate, gabapentin laurate, gabapentin lauryl sulfate, gabapentin decyl sulfate, and gabapentin myristyl sulfate.

Exemplary alkyl sulfates and salts of alkyl sulfates (eg, sodium, potassium, magnesium, etc.) contain from 6 to 18 carbon atoms, more preferably 8 to 16 and even more preferably 10 to 14 carbon atoms. Preferred alkyl sulfates include octyl sulfate, lauryl sulfate, myristyl sulfate. The formation of complexes of gabapentin or pregabalin with benzenesulfonic acid, benzoic acid, fumaric acid and salicylic acid or salts of these acids is also conceivable.

Gabapentin and pregabalin are zwitterionic compounds, making interactions between positively and negatively charged groups possible. In one embodiment, a transport moiety is selected that is capable of interacting with the positively charged _NH3 ⁺ moieties of gabapentin and pregabalin, as discussed with respect to Figures 3A-3C. Fatty acids and their salts, alkyl sulfates (saturated or unsaturated) and their salts (including especially sodium octyl sulfate, sodium decyl sulfate, sodium lauryl sulfate and sodium tetradecyl sulfate), benzenesulfonic acid and its salts, benzoic acid and its salts, fumaric acid and its salts, salicylic acid and its salts, or other pharmaceutically acceptable compounds containing at least one carboxyl group and their salts with the positive charge of gabapentin or pregabalin Group complexation.

In an alternative embodiment, a transport moiety is selected that is capable of interacting with the negatively charged COO-group of gabapentin or pregabalin. For example, primary aliphatic amines (saturated and unsaturated), diethanolamine, ethylenediamine, procaine, choline, tromethamine, meglumine, magnesium, aluminum, calcium, zinc, alkyl trimethyl Ammonium hydroxide, alkyltrimethylammonium bromide, benzalkonium chloride, and benzethonium chloride complex the negatively charged groups of gabapentin and pregabalin.

Continuing with Example 1A, a complex consisting of gabapentin-lauryl sulfate was prepared using dichloromethane (chloroform). Dichloromethane is only an exemplary solvent, other solvents that can dissolve the transport moiety and the drug are suitable. For example, fatty acids are soluble in chloroform, benzene, cyclohexane, ethanol (95%), acetic acid, and methanol. The solubility (g/L) of capric acid, lauric acid, myristic acid, palmitic acid and stearic acid in these solvents is shown in Table 1.

Table 1: Solubility of fatty acids at 20°C (g/L) fatty acid (number of carbon atoms) Chloroform benzene Cyclohexane 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 Palmitic Acid (16) 151 73 65 53.8 49.3 21.4 37 4 Stearic acid (18) 60 24.6 twenty four 15.4 11.3 1.2 1 <1

In one embodiment, the solvent used to form the complex is a solvent with a dielectric constant lower than that of water, preferably at least one-half that of water, more preferably at least one-third that of water. one. The dielectric constant is a measure of the polarity of the solvent, and the dielectric constants of exemplary solvents are shown in Table 2.

Table 2: Characteristics of Exemplary Solvents solvent boiling point, ℃ Dielectric constant water 100 80 Methanol 68 33 ethanol 78 24.3 1-propanol 97 20.1 1-butanol 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,N-Dimethylformamide (DMF) 153 38.3 Dimethylsulfoxide (DMSO) 189 47.2 Hexane 69 2.02 benzene 80 2.28 diethyl ether 35 4.34 Tetrahydrofuran (THF) 66 7.52 Dichloromethane 40 9.08 carbon tetrachloride 76 2.24

Solvents Water, methanol, ethanol, 1-propanol, 1-butanol, and acetic acid are polar protic solvents with hydrogen atoms attached to negatively charged atoms, typically oxygen atoms. The solvents acetone, ethyl acetate, methyl ethyl ketone, and acetonitrile are dipolar aprotic solvents that, in one embodiment, are preferred for use in the formation of the gabapentin (or pregabalin)-transport moiety complex. Dipolar aprotic solvents do not contain OH bonds, but generally have large bond dipole moments due to multiple bonds between carbon and oxygen or nitrogen. Most dipolar aprotic solvents contain C-O double bonds. Dipolar aprotic solvents reported in Table 2 have a dielectric constant at least half that of water.

Figure 3D shows a synthetic reaction scheme for the formation of the pregabalin lauryl sulfate complex. A salt form of pregabalin, eg, pregabalin hydrochloride, was prepared by mixing pregabalin with an aqueous solution of hydrochloric acid as described in Example IB. It is understood that other salts of pregabalin may be formed. Then, an alkyl sulfate such as lauryl sulfate is added. Although Figure 3D shows the sodium salt of lauryl sulfate, other salts are also suitable, such as potassium or magnesium alkyl sulfates. Pregabalin hydrochloride was mixed with sodium lauryl sulfate to form an ion pair of pregabalin and lauryl sulfate, represented in Figure 3D as a loose ion pair between the species. A solvent with a lower dielectric constant than water was added to the solution containing the ion pair of pregabalin and lauryl sulfate and mixed thoroughly and allowed to settle. The pregabalin-lauryl sulfate complex is extracted from the solvent phase (non-aqueous phase), and the solvent is usually removed by appropriate techniques including, but not limited to, evaporation, distillation, and the like.

The gabapentin-lauryl sulfate complex formed as described in Example 1A was analyzed by Fourier transform infrared spectroscopy (FTIR). The FTIR/ATR methodology is described in the Methods section below. For comparison, FTIR/ATR spectra of gabapentin, sodium lauryl sulfate, and a 1:1 molar ratio physical mixture of gabapentin and sodium lauryl sulfate (both components were dissolved in methanol and dried in air to form a solid film) were also generated , and the results are shown in Figures 4A-4D. The spectrum of gabapentin is shown in Figure 4A, with peaks corresponding to NH and COO moieties indicated. The spectrum of sodium lauryl sulfate is shown in Fig. 4B, and a major doublet corresponding to the SO moiety was observed between 1300-1200 cm ⁻¹ . The 1:1 molar mixture of gabapentin hydrochloride and sodium lauryl sulfate in water is shown in Figure 4C, and it is obvious that the characteristic peak of gabapentin is obviously attenuated and the SO peak (1300-1200cm ^-1 ) of sodium lauryl sulfate is broadened. Figure 4D shows the FTIR spectrum of the complex formed using the procedure of Example 1A, wherein the 2 peaks corresponding to the COO-group of gabapentin disappeared and were replaced by the peak of the COOH group of the gabapentin lauryl sulfate complex, Indicates that the charge of COO- is blocked. Distortion of the NH moiety of gabapentin (with a shift of 15 cm ⁻¹ ) was observed in the gabapentin lauryl sulfate spectrum. The shift of the NH bond band indicates the protonation of the NH group in the resulting complex. As shown in the spectrum of the gabapentin complex, the peak at 1250 cm ⁻¹ representing the SO absorption in the sodium lauryl sulfate spectrum was shifted by 30 cm ⁻¹ , suggesting the interaction of gabapentin with the sulfate group of sodium lauryl sulfate. FTIR scans revealed that gabapentin forms a complex that is distinct from a physical mixture of the two components.

Without wishing to be bound by a specific understanding of the mechanism, the inventors reason as follows. When loose ion pairs are placed in a polar solvent environment, it is assumed that the polar solvent molecules themselves insert into the spaces occupied by ionic bonds, thereby promoting the separation of the bonded ions. A solvation shell can form around a free ion, which contains polar solvent molecules electrostatically bound to the free ion. The solvation shell thus prevents the free ion from forming any form of, but loose ion-pair ionic bond with another free ion. Under conditions where multiple types of counterions are present in polar solvents, any particular loose ion pair may be relatively sensitive to counterion competition.

This effect is more pronounced when the polarity is enhanced, which is expressed by the dielectric constant of the solvent. Based on Coulomb's law, the force between two ions charged (q1) and (q2) and separated by a distance (r) in a medium of dielectric constant (e) is: $f=-\frac{q_1{\mathrm{<figure-callout\; id="2"\; label="q"\; filenames="A20048003917100481.png,A20048003917100491.png"\; state="\{\{state\}\}">q</figure-callout>}}_2}{4{\mathrm{\&pi;\&epsiv;}}_0{\mathrm{\&epsiv;r}}^2}$ (Equation 2)

where _ε0 is the space permittivity. The equation shows the importance of the dielectric constant (ε) for the stability of loose ion pairs in solvents. In aqueous solutions of high dielectric constant (ε = 80), electrostatic attractive forces are significantly reduced if water molecules attack the binding of ions and separate oppositely charged ions.

Therefore, high dielectric constant solvent molecules, once present in the vicinity of an ionic bond, attack the ionic bond and eventually break the bond. Such unbonded ions are then free to move in the solvent. These properties define loose transitions.

Tight ion pairs form differently than loose ion pairs and thus have different properties from loose ion pairs. Tight ion pairs are formed by reducing the number of polar solvent molecules in the bonding space between two ions. This allows the ions to move closer together, forming bonds that are significantly stronger than loose ion-pair bonds, but are still considered ionic. Disclosed more fully herein, tight ion pairs are obtained using less polar solvents than water to reduce entrapment of polar solvents between ions.

For an additional discussion of loose and tight transitions, see D. Quintanar-Guerrero et al., Pharm. Res., 14 (2):119-127 (1997).

Chromatographic methods can also be used to observe the difference between loose and tight transitions. Using reversed-phase chromatography, loose ion pairs can be easily separated under conditions that do not separate tight ion pairs.

Stronger chemical bonds can also be produced according to the invention by choosing the concentrations of cations and anions relative to each other. For example, in the case where the solvent is water, cations (bases) and anions (acids) can be selected to achieve stronger mutual attraction. If a weaker bond is desired, a weaker attractor can be selected.

To understand the transport of molecules across such membranes, biological membrane sections can be modeled as approximating the first order of a lipid bilayer. Transport across lipid bilayer fractions (as opposed to active transport etc.) is unfavorable for ions due to poor fractionation. Various investigators have suggested that neutralizing the charge of these ions increases transmembrane transport.

In the "ion pair" theory, the ionic drug moiety pairs with the opposite ion of the transport moiety to "hide" the charge and make the resulting ion pair more mobile in the lipid bilayer. This approach has attracted a great deal of attention and research, with particular focus on enhancing the absorption of orally administered drugs across the intestinal epithelium.

Although ion pairs have attracted much attention and research, they have not been met with much success. For example, ion pairing of two antiviral compounds was found to cause increased uptake not due to effects on ion pair transport across cells but on monolayer integrity (J. Van Gelder et al., Int. J. of Pharmaceuticals, 186 : 127-136 (1999). The authors reasoned that the formation of ion pairs may not be very effective in enhancing the transport of charged hydrophilic compounds across epithelial cells because competition with other ions found in vivo can destroy the beneficial effects of counterions. Other The authors have pointed out that ion-pair absorption experiments do not always point to a clear mechanism (D. Quintanar-Guerrero et al., Pharm. Res., 14(2):119-127 (1997)).

The inventors have unexpectedly discovered that a problem with these ion pair absorption experiments is that they use loose ion pairs instead of tight ion pairs for the experiments. Indeed, many ion-pair absorption absorption experiments published in the art do not even clearly distinguish the difference between loose and tight ion-pairs. The skilled artisan would in fact have to distinguish between the disclosed loose ion pairs by reviewing the published methods of preparing the ion pairs and noting that these disclosed preparation methods are for loose ion pairs rather than tight ion pairs. Loose ion pairs are relatively permissive to competition of counter ions and are prone to solvent-mediated (eg, water-mediated) breaking of ionic bonds that bind loose ion pairs. Thus, when the drug moiety of the ion pair reaches the membrane wall of the intestinal epithelial cell, it may or may not bind to the transport moiety as a free ion pair. The probability of an ion pair existing near the membrane wall depends on the ionic bonds that keep the ions together, but more on the respective local concentrations of the two ions. The rate of absorption of the uncomplexed drug moiety may not be affected by the uncomplexed transport moiety if the two moieties are not bound when they are close to the enterocyte membrane wall. So loose ion pairs may have only a limited effect on absorption compared to drug moieties administered alone.

In contrast, the complexes of the present invention have more stable linkages in the presence of polar solvents such as water. The inventors therefore reasoned that by forming a complex the drug moiety and the transport moiety would be more likely to associate in ion-pair form when they are close to the membrane wall. This association increases the chances that the charge of the moiety will be buried, making it easier for the resulting ion pair to cross the cell membrane.

In one embodiment, the complex comprises tight ion-pair bonds between the drug moiety and the transport moiety. As discussed herein, tight ions are more stable than loose ion pairs, thereby increasing the likelihood that drug moieties and transport moieties will associate as ion pairs when they approach the membrane wall. This association increases the chances that the moiety's charge will be masked, making it easier for the tightly ion-pair bound complex to cross the cell membrane.

It should be noted that the complexes of the present invention may improve absorption throughout the GI tract, rather than just the lower GI tract, relative to the non-complexed drug moiety, since the complexes are generally expected to improve transport across cellular channels, And not just to improve transit in the lower GI tract. For example, if the drug moiety is a substrate for an active transporter that occurs primarily in the upper gastrointestinal tract, the complex formed by the drug moiety can still serve as a substrate for the transporter. Thus, the total transport can be the sum of the amounts transported by the transporter plus the improved transcellular transport provided by the present invention. In one embodiment, complexes of the invention improve absorption in the upper GI tract, lower GI tract, and both upper and lower GI tracts.

In studies carried out in support of the present invention, the absorption of gabapentin-lauryl sulfate complex in the lower gastrointestinal tract in vivo was characterized using the rat flush-ligated colon model. As described in Example 2, doses of 10 mg gabapentin/rat were intubated into the ligated colons of test rats as gabapentin-lauryl sulfate complex or neat gabapentin (n=3 per group). Group 3 rats (n=3) were given 1 mg gabapentin intravenously. Blood samples were drawn periodically to analyze gabapentin concentrations. The data are shown in Figure 5.

Referring to Figure 5, intravenously administered gabapentin (triangles) had high initial plasma concentrations and rapidly decreased concentrations over the first 15 minutes. Slow drug absorption was seen when gabapentin was administered as an intracolonic bolus (round). In contrast, when the drug was administered to the lower GI tract in the form of the gabapentin-lauryl sulfate complex (diamonds), rapid drug absorption was seen, with Cmax observed 1 hour after intubation.

The pharmacokinetic parameters of this study are shown in Table 3. The area under the curve (AUC) was determined from 1 mg gabapentin/rat for each gabapentin dosage form from time 0 to time infinity, where time infinity was estimated by assuming a log-linear decay. Gabapentin bioavailability is expressed as a percentage of the gabapentin concentration produced by intravenous administration.

table 3 Drug form (route of administration) AUC∞(ng h/mL-mg) bioavailability(%) Gabapentin (intravenous) 6090.3 100 Gabapentin (colon) 301.4 4.9 Gabapentin Lauryl Sulfate Complex (Colon) 3854.1 63.3

When the complex of gabapentin and lauryl sulfate was administered to the lower gastrointestinal tract in complex form, the bioavailability of the complex was significantly improved relative to the neat drug, so that it is clearly seen that the complex provides enhanced colonic absorption. The bioavailability of the gabapentin-lauryl sulfate complex was improved 13-fold relative to that of the neat drug. Accordingly, the present invention contemplates compounds that are complexes of gabapentin (or pregabalin) and a transport moiety, wherein the complex provides at least 5-fold, more preferably Colonic absorption of at least 10-fold, and more preferably at least 12-fold, as evidenced by gabapentin (or pregabalin) bioavailability as determined by gabapentin (or pregabalin) plasma concentration. Thus, colonic absorption of gabapentin (or pregabalin) into the blood is significantly enhanced when gabapentin (or pregabalin) is administered as a gabapentin (or pregabalin)-transport moiety complex.

Another study was performed by placing gabapentin or gabapentin-lauryl sulfate complex in the duodenum of rats as described in Example 3. The doses of 5 mg/rat, 10 mg/rat, and 20 mg/rat were administered and blood samples were taken to determine the gabapentin concentration as a function of time. Another group of test animals received gabapentin or gabapentin-lauryl sulfate complex intravenously. The results are shown in Figures 6A-6C.

Figure 6A shows gabapentin plasma concentrations in ng/mL in animals treated with neat gabapentin intravenously (triangles) and intraduodenally at doses of 5 mg (circles), 10 mg (squares), and 20 mg (diamonds). Increases in blood levels with increasing doses were observed in animals administered via intubation into the duodenum. Naturally, the lower plasma drug concentrations in animals treated intravenously (triangles) were due to lower drug doses.

Figure 6B shows the results for animals with gabapentin-lauryl sulfate complex administered intravenously (triangles) and directly into the duodenum at 5 mg (circles), 10 mg (squares) and 20 mg (diamonds). Although absolute blood concentrations in animals receiving the gabapentin-lauryl sulfate complex were lower than in animals treated with gabapentin, the data show that absorption of gabapentin from the complex is increased relative to absorption of neat drug, possibly due in part to L - The amino acid transport system is unsaturated and/or the complex increases transport by other mechanisms. The comparison of blood concentrations between the 5 mg and 10 mg doses and between the 10 mg and 20 mg doses can be clearly seen in Figures 6A and 6B, where gabapentin administered in complex form showed a greater increase in blood concentrations with increasing doses.

Figure 6C shows the percent bioavailability of gabapentin administered to the duodenum of rats as neat drug (inverted triangles) or gabapentin lauryl sulfate complex (circles). The percent bioavailability was determined relative to intravenous administration of gabapentin. At the 20 mg dose, the gabapentin-lauryl sulfate complex showed higher bioavailability relative to the neat drug. The increased bioavailability at higher doses may be due to the increased absorption provided by the complex, where absorption in the gastrointestinal tract is not limited to the absorption of the complex through the L-amino acid transport system, but also through transcellular and paracellular Cellular mechanisms take place.

Table 4 shows the pharmacokinetic analysis of this study in which the area under the curve was determined from 0 to 4 hours and normalized to the 1 mg dose of gabapentin/rat. A log-linear decay relative to the data for gabapentin (iv) at the 4 hour point was assumed from the data measured for the first 3 hours. The percent bioavailability is relative to the percent bioavailability of gabapentin administered intravenously.

Table 4 drug form Dose (mg/kg±sd) AUC(0～4h, ng·h/ml-mg±sd) ^* bioavailability(%) Gabapentin (intravenous) 1 2727.1±259.1 100.0 Gabapentin (duodenal) 14.8±0.1 1705.2±257.2 62.5±9.4 Gabapentin (duodenal) 30.6±1.7 1205.7±276.3 44.2±10.1 Gabapentin (duodenal) 59.8±1.7 726.1±223.9 26.2±8.2 Gabapentin Lauryl Sulfate (Duodenal) 14.0±0.1 1604.3±479.1 58.8±17.6 Gabapentin Lauryl Sulfate (Duodenal) 29.1±1.1 1182.2±267.9 43.3±9.8 Gabapentin Lauryl Sulfate (Duodenal) 58.1±2.3 1033.9±88.9 37.9±3.3

^* Normalized to 1 mg gabapentin/kg dose

AUC and bioavailability data showed that colonic absorption of gabapentin improved with increasing dose when the drug was delivered as a gabapentin-transport moiety complex.

Although the experimental data are based on gabapentin, it should be understood that the findings extend to pregabalin, an analog of gabapentin. Examples 4 and 5 describe methods for determining the in vivo absorption of pregabalin-lauryl sulfate complex.

III. Exemplary Dosage Forms and Methods of Use

The complexes described above provide enhanced absorption in the gastrointestinal tract and particularly in the lower gastrointestinal tract of rats. The complex dosage forms and methods of treatment using the complexes and their enhanced colonic absorption will now be described. It should be understood that the dosage forms described below are examples only. It should also be understood that the dosage forms are equally suitable for gabapentin, pregabalin or mixtures thereof. Although in the discussion below, reference is made to gabapentin; it should be understood that the discussion applies to pregabalin as well.

A number of dosage forms are available for the gabapentin-transport moiety complex. As discussed above, the dosage form provides a once-daily dose for at least about 12 hours, more preferably at least 15 hours, and still more preferably at least about 20 hours of therapeutic effect. Dosage forms can be configured and formulated according to any design that delivers the desired dose of gabapentin. Typically, the dosage form is administered orally and is similar in size and shape to a conventional tablet or capsule. Orally administrable dosage forms may be prepared according to one of a variety of methods. For example, the dosage form can be prepared as a diffusion system such as a reservoir device or matrix device, a dissolution system such as an encapsulated dissolution system (including, for example, "tiny time pills" and beads and matrix dissolution systems and diffusion/ The combination of a dissolution system and an ion exchange resin system is described in Remington's Pharmaceutical Sciences, 18 ^th Ed., pp. 1682-1685 (1990).

A specific example of a dosage form suitable for a gabapentin-transport moiety complex is an osmotic dosage form. Typically, osmotic dosage forms use osmotic pressure to create a driving force for at least partial penetration of a liquid into a compartment formed by semipermeable walls that allow free diffusion of the liquid but not the drug or osmotic agent, if present. An advantage of osmotic systems is that they operate independently of pH and thus continue to operate at an osmotically determined rate throughout extended periods of time, even as the dosage form passes through the GI tract and encounters different microenvironments with significantly different pH values. A review of these dosage forms can be found in Santus and Baker, "Osmotic drug delivery: a review of the patent literature," Journal of Controlled Release, 35 : 1-21 (1995). Osmotic dosage forms are also described in detail in the following U.S. Patents, each of which is incorporated herein by reference: Nos.

An exemplary dosage form referred to in the art as an elementary osmotic pump dosage form is shown in FIG. 11 . The dosage form 20 shown in cross-section is also referred to as a primary osmotic pump dosage form, consisting of a semi-permeable wall 22 surrounding and surrounding an inner compartment 24 . The inner compartment comprises a single component layer, referred to herein as drug layer 26, comprising a mixture of gabapentin-transport moiety complex 28 and selected excipients. The excipients are adjusted to provide an osmotically active gradient that acts to attract fluid from the outside in through the wall 22, upon infiltration of the fluid to form a releasable gabapentin-transport moiety complex formulation. Excipients may comprise suitable suspending agents (also referred to herein as pharmaceutical carriers 30 ), binders 32 , lubricants 34 and osmotically active agents known as osmolytes 36 . Exemplary raw materials for each of these ingredients are provided below.

The semi-permeable wall 22 of the osmotic dosage form is permeable to passing liquids on the outside, such as water and biological fluids, but substantially impermeable to passing components in the inner compartment. The materials used to form the wall are essentially non-erodible and substantially insoluble in biological fluids during use of the dosage form. Representative polymers that form a semipermeable wall include homopolymers and copolymers, such as cellulose esters, cellulose ethers, and cellulose ester-ethers. Channel modifiers may be mixed with the wall forming materials to adjust the liquid permeability of the walls. For example, agents that produce a significant increase in the penetration of liquids such as water are often substantially hydrophilic, while those that produce a significant decrease in the penetration of water are substantially hydrophobic. Exemplary channel modulators include polyols, polyalkylene glycols (glycols), polyalkylene glycols (polyalkylenediols), alkylene glycol polyesters, and the like.

In operation, the osmotic gradient across the wall 22 due to the presence of the osmotically active agent causes gastric fluid to be absorbed across the wall, swelling the drug layer and forming a releasable formulation containing the gabapentin-transport moiety complex (e.g. solutions, suspensions, slurries, or other flowable compositions). The releasable gabapentin-transport moiety complex formulation is released through outlet 38 as the liquid continues into the inner compartment. Even as the complex-containing formulation is released from the dosage form, fluid continues to be drawn into the lumen, driving continued release. In this way, the gabapentin-transport moiety complex is released in a stable, sustained manner over an extended period of time.

Example 6A describes the preparation of the gabapentin-transporter moiety complex and Example 6B describes the preparation of the pregabalin-transporter moiety complex in the dosage form shown in FIG. 7 .

Figure 8 is a schematic diagram of another exemplary osmotic dosage form. Such dosage forms are described in detail in US Patent Nos. 4,612,008, 5,082,668, and 5,091,190, which are incorporated herein by reference. Briefly, the dosage form 40 shown in cross-section has a semi-permeable wall 42 defining an interior compartment 44 . The inner compartment 44 contains a bilayer compressed core with a drug layer 46 and a push layer 48 . As will be described below, the pusher layer 48 is a displacement displacement composition placed in the dosage form, during use the pusher layer expands and the material forming the drug layer exits the dosage form through one or more outlets such as outlet 50 . The push layer can be placed in aligned layers in contact with the drug layer, as shown in Figure 8, or the push layer can have one or more intermediate layers separating the push layer and the drug layer.

Drug layer 46 contains a gabapentin-transport moiety complex mixed with selected excipients such as those discussed above with reference to FIG. 7 . An exemplary dosage form may comprise a drug layer consisting of a ferrous-lauryl ester complex, polyethylene oxide as a carrier, sodium chloride as an osmotic agent, hydroxypropylmethylcellulose as a binder, and Lubricant magnesium stearate.

The propulsion layer 48 comprises an osmotically active ingredient, such as one or more polymers, known in the art as osmopolymers, that absorb and swell aqueous or biological fluids. Osmopolymers are swellable hydrophilic polymers that interact with water and aqueous biological fluids and swell or expand to a large extent, typically exhibiting a 2-50 fold increase in volume. The osmopolymer may be non-crosslinked or crosslinked, in preferred embodiments the osmopolymer is at least lightly crosslinked to produce a polymer network which is large and entangled so as not to be easily expelled from the dosage form during use. Examples of polymers that may be used as osmopolymers are provided in the above references detailing osmotic dosage forms. Common osmopolymers are polyalkylene oxides such as polyethylene oxide and poly(alkali carboxymethylcellulose) where the base is sodium, potassium or lithium. Other excipients such as binders, lubricants, antioxidants and colorants may also be included in the push layer. In use, when liquid is absorbed through the semipermeable wall, the osmopolymer swells and pushes against the drug layer causing release of the drug from the dosage form through the outlet.

The push layer may also comprise components mentioned as binders, generally cellulose or vinyl polymers such as polyn-vinylamide, polyn-vinylacetamide, polyvinylpyrrolidone, polyn-vinylcaprolactone ( caprolactone), polyn-vinyl-5-methyl-2-pyrrolidone, etc. The push layer may also include a lubricant, such as sodium stearate or magnesium stearate, and an antioxidant to inhibit oxidation of the ingredients. Representative antioxidants include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, mixtures of 2- and 3-tert-butyl-4-hydroxyanisole, and butylated hydroxytoluene.

Osmotic agents may also be incorporated into the drug layer and/or push layer ester of an osmotic dosage form. The presence of an osmotic agent establishes a gradient of osmotic activity across the semipermeable wall. Exemplary osmotic agents include salts such as sodium chloride, potassium chloride, lithium chloride, and the like, and sugars such as raffinose, sucrose, glucose, lactose, and carbohydrates.

With continued reference to FIG. 8, the dosage form may optionally include an overcoat (not shown) for color marking the dosage form according to dose or to provide immediate release of gabapentin, pregabalin or other drug.

In use, water flows across the wall into the push and drug layers. The pusher layer picks up fluid and begins to expand, and then pushes the drug layer 44 to expel the material in that layer through the outlet and into the gastrointestinal tract. The push layer 48 is designed to absorb fluid and continue to expand, thereby allowing the dosage form to continue to expel drug from the drug layer throughout the gastrointestinal tract. In this way, the dosage form provides the gabapentin-transport moiety complex to the gastrointestinal tract for 15 to 20 hours, or substantially throughout the duration of the dosage form's passage through the gastrointestinal tract. Since the gabapentin-transport moiety complex is absorbed in both the upper and lower gastrointestinal tracts, administration of the dosage form during passage of the dosage form through the gastrointestinal tract delivers gabapentin into the bloodstream.

Another exemplary dosage form is shown in FIG. 9 . The osmotic dosage form 60 has a three-layer core 62 comprising three layers: a first layer of gabapentin 64, a second layer of gabapentin-transport moiety complex 66 and a third layer 68 known as the push layer. Dosage forms of this type are described in detail in US Patent Nos. 5,545,413, 5,858,407, 6,368,626 and 5,236,689, which are incorporated herein by reference. As indicated in Example 7, the first layer of a three-layer dosage form was prepared containing 85.0 wt% gabapentin, 10.0 wt% polyethylene oxide of 100,000 molecular weight, 4.5 wt% polyvinylpyrrolidone with a molecular weight of about 35,000 to 40,000, and 0.5 wt% %Magnesium stearate. The second layer comprised 93.0 wt% gabapentin-transport moiety complex (prepared as described in Example 1A), 5.0 wt% polyethylene oxide with a molecular weight of 5,000,000, 1.0 wt% polyvinylpyrrolidone with a molecular weight of about 35,000 to 40,000, and 1.0 wt% %Magnesium stearate.

The push layer consists of 63.67% by weight of polyethylene oxide, 30.00% by weight of sodium chloride, 1.00% by weight of iron oxide, 5.00% by weight of hydroxypropyl methylcellulose, 0.08% by weight of butylated hydroxytoluene and 0.25% Composition of magnesium stearate by weight. The semipermeable wall consisted of 80.0% by weight cellulose acetate and 20.0% polyethylene oxide-polypropylene oxide copolymer with an acetyl content of 39.8%.

The dissolution rate of dosage forms such as those shown in Figures 7-9 can be determined according to the procedure set forth in Example 8. Typically, the release of the drug formulation from the dosage form begins after exposure to an aqueous environment, wherein, depending on the dosage form, the drug formulation contains gabapentin or a gabapentin-transport moiety complex. For example, in the dosage form shown in Figure 7, the gabapentin-transport moiety complex is released upon exposure to an aqueous environment and persists for the lifetime of the device. The dosage form shown in Figure 9 initially releases gabapentin in the drug layer adjacent to the outlet, followed by release of the gabapentin-transport moiety complex.

10A-10C illustrate another exemplary dosage form known in the art and described in US Patent Nos. 5,534,263, 5,667,804, and 6,020,000, which are specifically incorporated herein by reference. Briefly, Figure 10A shows a cross-sectional view of dosage form 80 prior to ingestion into the gastrointestinal tract. The dosage form comprises a cylindrical matrix 82 containing a gabapentin-transport moiety complex. The ends 84, 86 of the matrix 82 are preferably of rounded convex shape to ensure easy ingestion. Bands 88, 90 and 92 concentrically surround the cylindrical matrix, these bands being formed from a material that is relatively insoluble in the aqueous environment. Suitable materials are listed in the patents noted above and in Example 9 below.

After ingestion of dosage form 80, the areas of matrix 82 between bands 88, 90, 92 begin to erode, as shown in Figure 10B. Erosion of the matrix initiates release of the gabapentin-transport moiety complex into the fluid environment of the gastrointestinal tract. As the dosage form continues to transit the GI tract, the matrix continues to erode, as shown in Figure 10C. At this point, erosion of the matrix has progressed to the point where the dosage form breaks into three pieces 94,96,98. Erosion continues until the matrix portion of each fragment has been completely ablated. The bands 94, 96, 98 are then expelled from the gastrointestinal tract.

It should be understood that the dosage forms depicted in Figures 7-10 are only exemplary of the various dosage forms designed and capable of releasing the gabapentin-transport moiety complex into the lower gastrointestinal tract. Those skilled in the pharmaceutical art will identify suitable other dosage forms.

In another aspect, the present invention provides a method of administering gabapentin to a patient by administering a composition comprising a complex of gabapentin and a transport moiety characterized by a close ion between gabapentin (or pregabalin) and the transport moiety right key. Compositions comprising the complex and a pharmaceutically acceptable vehicle are generally administered to the patient by oral administration.

The dosage administered is generally adjusted according to the age, weight and condition of the patient, taking into account the dosage form and the desired result. In general, dosage forms and compositions of the gabapentin-transport moiety complex are administered in amounts recommended for gabapentin (Neurontin( ^R )) therapy, as set forth in the Physician's Desk Reference. Typical doses for controlling seizures in epileptic patients are 900-1800 mg per day. Typical doses for neuropathic pain relief are 600-3600 mg per day (Backonja, M., Clinical Therapies, 23 (1) (2003)). It is to be understood that these dosage ranges represent approximate ranges and that the increased absorption afforded by the complex will vary the required dosage.

With regard to pregabalin, the dose of administration will also be adjusted according to the age, weight and condition of the patient, taking into account the dosage form and the desired results. Generally, a dose of at least about 300 mg per day is provided and increased as needed to relieve perceived pain. Pain reduction can be measured with a digitized pain rating scale, such as the Short-Form McGill Pain Questionnaire (Dworkin, RH et al., Neurology, 60 :1274 (2003)).

From the foregoing it will be seen that the various objects and features of the present invention are satisfied. Complexes containing gabapentin or pregabalin and a transport moiety (gabapentin (or pregabalin) is associated with the transport moiety by non-covalent tight ion-pair bonds) facilitate drug absorption in the gastrointestinal tract. The complex is prepared by a novel method in which gabapentin or pregabalin is brought into contact with a transport moiety (such as an alkyl sulfate or a fatty acid) soluble in a solvent less polar than water, as evidenced by a low dielectric constant, for example. polarity. Exposure of the drug to the transport moiety-solvent mixture results in the formation of a complex between the drug (gabapentin or pregabalin) and the transport moiety, wherein the two are associated by a tight ion-pair bond.

IV. Embodiment

The following examples further illustrate the invention described herein and are in no way intended to limit the scope of the invention.

method:

1. FTIR: Fourier transform spectroscopic examination was performed on a Perkin-Elmer Spectrum 2000 spectroscopic system equipped with an attenuated total reflectance (ATR) accessory and a liquid nitrogen cooled MCT (mercury cadmium telluride) detector.

Example 1

Preparation of gabapentin-transport moiety complexes and pregabalin-transport moiety complexes

Preparation of gabapentin-transport moiety complexes

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

2. Add 5 mmol gabapentin (0.86 g) to the solution from step 1. The mixture was stirred at room temperature for 10 minutes. Gabapentin hydrochloride is formed.

3. Add 5 mmol sodium lauryl sulfate (1.4 g) to the aqueous solution of step 2. The mixture was stirred at room temperature for 20 minutes.

4. Add 50 mL of dichloromethane to the solution from step 3. The mixture was stirred at room temperature for 2 hours.

5. Transfer the mixture from step 4 to a separatory funnel and allow it to settle for 3 hours. Two phases form, a lower phase of dichloromethane and a higher phase of water.

6. Separate the high and low phases from step 5. The lower phase dichloromethane was recovered and evaporated to dryness at room temperature, followed by drying in a vacuum oven at 40 °C for 4 hours. Gabapentin-lauryl sulfate complex (1.9 g) was obtained. The overall yield was 87% relative to the theoretical amount calculated using starting amounts of gabapentin and sodium lauryl sulfate.

Preparation of pregabalin-transport moiety complex

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

2. Add 5 mmol of pregabalin (0.80 g) to the solution of step 1. The mixture was stirred at room temperature for 10 minutes. Pregabalin hydrochloride is formed.

3. Add 5 mmol sodium lauryl sulfate (1.4 g) to the aqueous solution of step 2. The mixture was stirred at room temperature for 20 minutes.

4. Add 50 mL of dichloromethane to the solution from step 3. The mixture was stirred at room temperature for 2 hours.

5. Transfer the mixture from step 4 to a separatory funnel and allow it to settle for 3 hours. Two phases form, a lower phase of dichloromethane and a higher phase of water.

7. Separate the high and low phases from step 5. The lower phase dichloromethane was recovered and evaporated to dryness at room temperature, followed by drying in a vacuum oven at 40 °C for 4 hours. A pregabalin-lauryl sulfate complex (2.1 g) was obtained.

Example 2

In vivo colonic absorption in a rat irrigated and ligated colon model

An animal model commonly known as "flush-ligated colon model" or "intracolonic ligated model" is used. Fasted 0.3-0.5 kg Sprague-Dawley male rats were anesthetized and the segment closest to the colon was isolated. Flush the fecal material from the colon. Both ends of the colon segment are ligated while a catheter is placed in the lumen and removed intraperitoneally and placed on the skin for delivery of the test formulation. The contents of the colon were rinsed and the colon was returned to the animal's abdominal cavity. According to the set experiment, the test preparation was added after the segments were perfused with 1 mL/kg of 20 mM sodium phosphate buffer, pH 7.4, to more accurately mimic the actual colonic environment in clinical situations.

Rats (n=3) were allowed to equilibrate for approximately 1 hour following surgical preparation and prior to exposure to each test formulation. Gabapentin-lauryl sulfate complex or gabapentin was given by intracolonic bolus injection and delivered as 10 mg gabapentin-lauryl sulfate or 10 mg gabapentin/rat. Blood samples were obtained from the jugular catheter at 0, 15, 30, 60, 90, 120, 180, and 240 minutes and analyzed for gabapentin concentrations. At the end of the 4 h test period, the rats were euthanized with an overdose of pentobarbital. A segment of colon from each rat was cut and opened longitudinally along the mesenteric abutment. Visually inspect each bowel segment for irritation and any obvious abnormalities. Place the severed colon on graph paper and measure the approximate colon surface area. There were no histopathological changes in the mucous membranes of any test rats.

Rats in the control group (n=3) were treated intravenously with gabapentin at a dose of 1 mg/rat. Blood samples were drawn at the same times indicated above for analysis of gabapentin concentrations.

Gabapentin plasma concentrations for each test animal and mean plasma concentrations for animals in each test group are shown in Tables A-C. Figure 5 shows the mean gabapentin concentrations for each test group as a function of time.

Table A Gabapentin - given intravenously 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

Form B Gabapentin - Colon Intubation 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

Form C Gabapentin Lauryl Sulfate - Colon Intubation 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

Example 3

Absorption in the body

28 large rats were randomly divided into 7 test groups (n=4). The gabapentin or gabapentin-lauryl sulfate complex prepared as described in Example 1A was intubated to the beginning of the duodenum of rats at doses of 5 mg/rat, 10 mg/rat and 20 mg/large, respectively. mouse. The remaining test group received 1 mg/kg gabapentin intravenously.

Blood samples from each animal were drawn after 4 hours and analyzed for gabapentin content. The results are shown in Tables D-H and Figures 6A-6C.

Form D Gabapentin lauryl sulfate, duodenal dose 5mg/rat time (h) Rat 1(ng/mL) Rat 2(ng/mL) Rat 3(ng/mL) Rat 4(ng/mL) average 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

Form E Gabapentin lauryl sulfate, duodenal dose 10mg/rat time (h) Rat 1(ng/mL) Rat 2(ng/mL) Rat 3(ng/mL) Rat 4(ng/mL) average 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

Form F Gabapentin lauryl sulfate, duodenal dose 20mg/rat time (h) Rat 1(ng/mL) Rat 2(ng/mL) Rat 3(ng/mL) Rat 4 (mg/mL) average 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

Form G Gabapentin, duodenal dose 5mg/rat time (h) Rat 1(ng/mL) Rat 2(ng/mL) Rat 3(ng/mL) Rat 4(ng/mL) average 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

Form H Gabapentin, duodenal dose 10mg/rat time (h) Rat 1(ng/mL) Rat 2(ng/mL) Rat 3(ng/mL) Rat 4(ng/mL) average 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 missing 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, duodenal dose 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

Example 4

In Vivo Colonic Absorption Using a Rat Irrigated and Ligated Colon Model

An animal model commonly known as the "model of intracolonic ligation" is used. Fasted 0.3-0.5 kg Sprague-Dawley male rats were anesthetized and the segment closest to the colon was isolated. Flush the fecal material from the colon. Both ends of the colon segment are ligated while a catheter is placed in the lumen and removed intraperitoneally and placed on the skin for delivery of the test formulation. The contents of the colon were rinsed and the colon was returned to the animal's abdominal cavity. According to the set experiment, the test preparation was added after the segments were perfused with 1 mL/kg of 20 mM sodium phosphate buffer, pH 7.4, to more accurately mimic the actual colonic environment in clinical situations.

Rats (n=3) were allowed to equilibrate for approximately 1 hour following surgical preparation and prior to exposure to each test formulation. Pregabalin-lauryl sulfate complex or pregabalin was administered by intracolonic bolus injection and dosed at 10 mg pregabalin/rat. Blood samples were obtained from the jugular catheter at 0, 15, 30, 60, 90, 120, 180, and 240 minutes and analyzed for pregabalin concentrations. At the end of the 4 h test period, the rats were euthanized with an overdose of pentobarbital. A segment of colon from each rat was cut and opened longitudinally along the mesenteric abutment. Visually inspect each bowel segment for irritation and any obvious abnormalities. Place the severed colon on graph paper and measure the approximate colon surface area.

Rats in the control group (n=3) were treated intravenously with pregabalin at a dose of 1 mg/rat. Blood samples were drawn at the same times indicated above.

Example 5

Absorption in the body

28 rats were randomly divided into 7 test groups (n=4). The pregabalin or pregabalin-lauryl sulfate complex prepared as described in Example 1B was intubated to the beginning of the duodenum of rats at a dose of 5 mg/rat and 10 mg/rat respectively and 20mg/rat. The remaining test group was given 1 mg/kg pregabalin intravenously.

Blood samples from each animal were drawn after a 4 hour period and analyzed for pregabalin content. Dose, AUC and bioavailability were determined using calculations similar to those used in Example 3 for gabapentin.

Example 6

       Preparation of dosage forms containing drug-transport moiety complexes

A. Gabapentin-transport moiety complex

The device shown in Figure 7 was prepared as follows. A compartment forming composition comprising 92.25% by weight gabapentin-transport moiety complex, 5% potassium carboxypolyethylene, 2% polyethylene oxide having a molecular weight of about 5,000,000, and 0.5% carbon dioxide was mixed together. silicon. Next, the mixture was passed through a 40 mesh stainless steel screen and then dry blended in a V-blender for 30 minutes to produce a homogeneous mixture. Next, pass 0.25% magnesium stearate through an 80 mesh stainless steel screen and blend for an additional 5 to 8 minutes. The homogeneous dry blended powder was then placed into a funnel and fed to a compartment forming compactor, and a known amount of the blend was compacted into a 5/8 inch oval shape designed for oral administration. The elliptical precompartments were then coated in an Accela-Cota( ^R ) wall forming coater with a wall forming composition containing 91% cellulose acetate (containing 39.8% acetyl groups) and 9 % polyethylene glycol 3350. After coating, the wall-coated drug compartments were removed from the coater and transferred to a drying oven to remove residual organic solvents used during wall formation. Next, the coating device was transferred to a 50° C. blast drying oven for drying for about 12 hours. Then, one or more outlets are formed in the wall of the device with a laser.

B. Pregabalin-transport moiety complex

The device shown in Figure 7 was prepared as follows. A compartment-forming composition comprising 92.25% by weight of pregabalin-transport moiety complex, 5% potassium carboxypolyethylene, 2% polyethylene oxide with a molecular weight of about 5,000,000, and 0.5% silica. Next, the mixture was passed through a 40 mesh stainless steel screen and then dry blended in a V-blender for 30 minutes to produce a homogeneous mixture. Next, pass 0.25% magnesium stearate through an 80 mesh stainless steel screen and blend for an additional 5 to 8 minutes. The homogeneous dry blended powder was then placed into a funnel and fed to a compartment forming compactor, and a known amount of the blend was compacted into a 5/8 inch oval profile designed for oral administration. The elliptical precompartments were then coated in an Accela-Cota( ^R ) wall forming coater with a wall forming composition containing 91% cellulose acetate (containing 39.8% acetyl groups) and 9 % polyethylene glycol 3350. After coating, the wall-coated drug compartments were removed from the coater and transferred to a drying oven to remove residual organic solvents used during wall formation. Next, the coating device was transferred to a 50° C. blast drying oven for drying for about 12 hours. Then, one or more outlets are formed in the wall of the device with a laser.

Example 7

Preparation of dosage forms containing gabapentin-transport moiety complex

A dosage form containing a gabapentin layer and a gabapentin-lauryl sulfate complex layer, as shown in FIG. 9 , was prepared as follows.

10 g of gabapentin, 1.18 g of polyethylene oxide with a molecular weight of 100,000, and 0.53 g of polyvinylpyrrolidone with a molecular weight of about 38,000 were dry mixed in a conventional mixer for 20 minutes to produce a homogeneous mixture. Next, with the mixer continuing to stir, 4 mL of denatured absolute ethanol was slowly added to the dry mixture of the 3 components. Mixing was continued for an additional 5 to 8 minutes. The combined wet composition was passed through a 16 mesh screen and dried overnight at room temperature. Then, the dry granules were passed through a 16 mesh screen and 0.06 g of magnesium stearate was added and all ingredients were dry blended for 5 minutes. Fresh pellets are ready for use in formulating the starting dose layer in the dosage form.

The dosage form containing the gabapentin-lauryl sulfate complex layer was prepared as follows. First, 9.30 g of the gabapentin-lauryl sulfate complex prepared as described in Example 1A, 0.50 g of polyethylene oxide with a molecular weight of 5,000,000, and 0.10 g of polyvinylpyrrolidone with a molecular weight of about 38,000 were dry mixed in a conventional mixer for 20 minutes to produce a homogeneous mixture. Next, denatured absolute ethanol was slowly added to the mixture and mixing was continued for 5 minutes. The combined wet composition was passed through a 16 mesh screen and dried overnight at room temperature. Then, the dry granules were passed through a 16 mesh screen and 0.10 g of magnesium stearate was added and all dry ingredients were dry blended for 5 minutes.

The push layer comprising the osmopolymer hydrogel composition was prepared as follows. First, 58.67 g of pharmaceutically acceptable polyethylene oxide with a molecular weight of 7,000,000, 5 g of Carbopol ^(R) 974P, 30 g of sodium chloride, and 1 g of iron oxide were sieved through a 40-mesh sieve, respectively. The screened ingredients were mixed with 5 g of hydroxypropylmethylcellulose of molecular weight 9,200 to produce a homogeneous mixture. Next, 50 mL of denatured absolute ethanol was slowly added to the mixture and mixing was continued for 5 minutes. Then, 0.080 g of butylated hydroxytoluene was added and mixing continued. Freshly prepared granules were passed through a 20 mesh screen and dried at room temperature (ambient temperature) for 20 hours. Pass the dry ingredients through a 20 mesh screen and add 0.25 g of magnesium stearate and mix all ingredients for 5 minutes.

A 3-layer dosage form was prepared as follows. First, 118 mg of the gabapentin composition was added to the punch and die set and tamped, then 511 mg of the gabapentin-lauryl sulfate composition was added to the mold as a second layer and tamped again. Next, 315 mg of the hydrogel composition was added and the 3 layers were compressed into a 9/32 inch (0.714 cm) diameter die assembly under 1 ton (1000 kg) of compression force to form a compact 3 layer core (tablet).

A semi-permeable wall-forming composition containing 80.0% by weight of cellulose acetate (containing 39.8% acetyl content) and 20.0% of a polyethylene oxide-polyoxypropylene copolymer with a molecular weight of 7680-9510 was prepared by making the ingredients at 80 : 20 wt/wt The composition was dissolved in acetone to give a 5.0% solids solution. The wall forming composition was sprayed on or around the 3-layer core to produce a 60 to 80 mg thick semi-permeable wall.

Next, a 40 mil (1.02 mm) outlet was laser drilled in the semi-permeable walled 3-layer tablet to bring the gabapentin layer into contact with the exterior of the delivery device. The dosage form is allowed to dry to remove any residual solvent and water.

Example 8

In Vitro Dissolution of Dosage Forms Containing Gabapentin-Transport Moiety Complexes

The in vitro dissolution rates of dosage forms prepared as described in Examples 4 and 5 were determined by placing the dosage forms in a sample holder attached to a metal coil on a USP Type VII bath indexer in a 37°C constant temperature water bath. An aliquot of the release medium was injected into the chromatographic system to determine the amount of gabapentin (or pregabalin) released into the medium-stimulated artificial gastric fluid (AGF) at each test interval.

Example 9

Preparation of dosage forms containing gabapentin-transport moiety complexes

The dosage forms represented in Figures 10A-10C are prepared as follows. Unit doses of extended release gabapentin-lauryl sulfate complex are prepared as follows. 200 g of gabapentin in the form of the gabapentin-lauryl sulfate complex was passed through a 40 mesh per inch sieve. 25 g of hydroxypropylmethylcellulose having a number average molecular weight of 9,200 g/mole and 15 g of hydroxypropylmethylcellulose having a molecular weight of 242,000 g/mole were screened through a sizing screen of 40 mesh per inch. Each of the celluloses contained an average hydroxyl group content of 8 weight percent and an average methoxy group content of 22 weight percent. The graded powder was tumble mixed for 5 minutes. Absolute ethanol was added to the mixture with stirring until a moist mass formed. Pass the wet mass through a 20 mesh per inch sizing screen. The resulting moist pellets were air dried overnight and passed through a 20 mesh screen again. 2 g of the tableting lubricant, magnesium stearate, were passed through an 80 mesh per inch sieve. The graded magnesium stearate is mixed with dry granules to form the final granulation.

733 mg of the final granule portion was placed in a cavity having an internal diameter of 0.281 inches. This part is compressed with a deep concave punch under a 1 ton pressure head to form a tablet with the appearance of a longitudinal capsule.

Capsules were fed into a Tait Capsealer Machine (Tait Design and Machine Co., Manheim, Pa.), where each capsule was printed with 3 bands. The tape forming material was 50 wt% ethyl cellulose dispersion (Surelease ^(R) , Colorcon, West Point, Pa.) and 50 wt% ethyl acrylate methyl methacrylate (Eudragit ^(R) NE 30D, RohmPharma, Weiterstadt, Germany). The strips are suitable as aqueous dispersions and excess water is distilled off in the presence of warm air. The diameter of the strips is 2 mm.

While the features and advantages of the present invention have been described and indicated by prior embodiments, those skilled in the pharmaceutical arts will appreciate that various modifications, changes, additions and omissions may be made to the methods described in the specification without departing from the spirit of the invention.

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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