Solid dosage formulations of narcotic drugs having improved buccal adsorption
US20070020186A1
2007-01-25
11/186,925
2005-07-22
Abstract:
The present invention provides solid dosage formulations of narcotic drugs with improved buccal adsorption. These improved characteristics are provided by the combination of the narcotic drug with an additional non-toxic soluble organic compound. The soluble organic compound contains a primary, secondary or tertiary amine group. The addition of this organic compound favorably alters the kinetics of mucosal penetration such that mucosal penetration times are decreased. This provides for a faster onset of action of the drug.
Inventors:
- Federico STROPPOLO 14 🇨🇭 Aldesago, Switzerland
- Shahbaz ARDALAN 3 🇨🇭 Maroggia, Switzerland
Assignee:
- ALPEX PHARMA S.A. 16 🇨🇭 Mezzovico, Switzerland
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Classification:
A61K9/0056 » CPC main
Medicinal preparations characterised by special physical form; Galenical forms characterised by the site of application; Mouth and digestive tract, i.e. intraoral and peroral administration Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
A61K9/2013 » CPC further
Medicinal preparations characterised by special physical form; Pills, tablets, discs, rods; Excipients; Inactive ingredients Organic compounds, e.g. phospholipids, fats
A61K31/4468 » CPC further
Medicinal preparations containing organic active ingredients; Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom; Non condensed pyridines; Hydrogenated derivatives thereof; Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
A61K47/18 » CPC further
Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient; Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
A61P25/04 » CPC further
Drugs for disorders of the nervous system Centrally acting analgesics, e.g. opioids
A61K31/485 IPC
Medicinal preparations containing organic active ingredients; Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom; Quinolines; Isoquinolines Morphinan derivatives, e.g. morphine, codeine
A61K31/445 IPC
Medicinal preparations containing organic active ingredients; Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom; Non condensed pyridines; Hydrogenated derivatives thereof Non condensed piperidines, e.g. piperocaine
A61K9/20 IPC
Medicinal preparations characterised by special physical form Pills, tablets, discs, rods
Description
The present invention concerns solid dosage formulations of narcotic drugs having improved buccal adsorption.
The formulations of the invention are characterized by the introduction in a buccal formulation of a soluble organic compound having a primary, secondary or tertiary amine group.
BACKGROUND OF THE INVENTIONBuccal formulations are more and more popular for drug administrations. They exhibit in fact several advantages in comparison with other solid dosage forms; in particular, buccal formulations dissolve in the oral cavity without requiring water for ingestion, allowing the buccal adsorption of drugs coming into contact with the oral mucosa in dissolved form. Sometimes, buccal administration does not unfortunately always allow to obtain a fast onset of action of the drug, as the result of difficulties of the drug to cross the skin barrier of mucosa and to penetrate into the blood stream.
DESCRIPTION OF THE INVENTIONSurprisingly, it has been found that adding a non-toxic amine to a buccal formulation, the penetration capacity of drugs is significantly improved, allowing to reach an higher and earlier blood concentration of drugs in comparison with formulations without amines.
The amount of amine required in the formulation ranges between 0.1 to 500% of the moles of active component(s), more preferably 0.5 to 300% and most preferably 1 to 200%.
Examples of amines used in order to improve bioavailability according to the invention include Histidine, Arginine, Lysine, Triethanolamine, Trimethylamine, Betaine, Pyrrolidine, Guanidine, Cysteamine, Taurine and derivatives and analogues thereof. Arginine is a preferred non-toxic amine.
Examples of active components that may be advantageously formulated in solid dosage form according to the invention include:
Alfentanil, Buprenorphine Butorphanol, Codeine, Diphenoxylate, Fentanyl, Heroin, Hydrocodone, Hydromorphone, Oxymorphone, Levophanol, Levallorphan, Loperamide, Meperidine, Morfine, Nalbuphine, Nalmefene, Nalorphine, Naloxone, Naltrexone, Remifentanyl, Sufentanil. Fentanyl is preferred.
The invention is illustrated by the following Examples:
EXAMPLE #1 Example #1APreparation of a Oral Dispersible Tablet Containing Amine (Arginine)
Oral dispersible tablets containing 200 mcg of Fentanyl were obtained as follows:
A) 1.05 g of Fentanyl and 50 g of PEG 600 were dissolved into 90 g of purified water.
B) 335.62 g of Sorbitol, 516.67 g of Mannitol, 26.67 g of aspartame and 10 g of Citric acid, were granulated together with a water solution containing PEG and Fentanyl citrate.
C) At the end of granulation and drying, 43.33 g of arginine free base and 16.67 g of magnesium stearate were added.
D) The product was blended until homogeneity and compressed in toroidal tablets having a diameter of 10 mm and weighing 300 mg each
Example #1BPreparation of an Oral Dispersable Tablet without Amine (Arginine)
Oral dispersible tablets containing 400 mcg of Fentanyl have been obtained as follows:
E) 2.1 g of Fentanyl and 50 g of PEG 600 was dissolved into 90 g of purified water.
F) 455.62 g of Sorbitol, 455.62 g of Mannitol, 26.67 g of aspartame and 10 g of Citric acid, were granulated together with a water solution containing PEG and Fentanyl citrate.
G) The product was blended until homogeneity and compressed in toroidal tablets having a diameter of 10 mm and weighing 300 mg each
EXAMPLE # 2A pharmacokinetic study was carried out on 6 fasting healthy volunteers treated with a buccal formulation prepared in accordance with example # 1A containing 200 mcg of Fentanyl. The results were compared with a pharmacokinetic study carried out on 6 healthy volunteers treated with a buccal formulation prepared in accordance with example # 1B containing 400 mcg of Fentanyl.
The results are reported in the following Table:
| Fentanyl | ||||
| strength per | ||||
| dosage | Tmax | Cmax | AUC | |
| Example # 1A | 200 mcg | 48 minutes | 496 pg/mL | 2430 |
| Example # 1B | 400 mcg | 35 minutes | 491 pg/mL | 3331 |
Despite the dose of Fentanyl administered in the tablets described in example # 1A (200 mcg) is 50% of the dose described in example #1B (400 mcg), the pharmacokinetic parameters are similar, demonstrating a dramatic improvement of the Fentanyl bioavailability for the formulation of the invention.
Claims
1. Solid dosage formulations of narcotic drugs in form of buccal tablets characterized by containing a non toxic amine.
2. Formulations according to claim 1, wherein the non-toxic amine is selected from Histidine, Arginine, Lysine, Triethanolamine, Trimethylamine, Betaine, Pyrrolidine, Guanidine, Cysteamine, Taurine and derivatives and analogues thereof.
3. Formulations according to claim 2 wherein the non-toxic amine is arginine.
4. Formulations according to claim 1 wherein the non-toxic amine is present in amounts ranging between 0.1 to 500% of the moles of active component(s), more preferably 0.5 to 300% and most preferably 1 to 200%.
5. Formulations according to claim 1 wherein the narcotic drug is selected from Alfentanil, Buprenorphine, Butorphanol, Codeine, Diphenoxylate, Fentanyl, Heroin, Hydrocodone, Hydromorphone, Oxymorphone, Levophanol, Levallorphan, Loperamide, Meperidine, Morfine, Nalbuphine, Nalmefene, Nalorphine, Naloxone, Naltrexone, Remifentanyl, Sufentanil.
6. Formulations according to claim 5 wherein the active ingredient is Fentanyl.