U.S. patent application number 11/186925 was filed with the patent office on 2007-01-25 for solid dosage formulations of narcotic drugs having improved buccal adsorption.
This patent application is currently assigned to ALPEX PHARMA S.A.. Invention is credited to Shahbaz Ardalan, Federico Stroppolo.
Application Number | 20070020186 11/186925 |
Document ID | / |
Family ID | 37440618 |
Filed Date | 2007-01-25 |
United States Patent
Application |
20070020186 |
Kind Code |
A1 |
Stroppolo; Federico ; et
al. |
January 25, 2007 |
Solid dosage formulations of narcotic drugs having improved buccal
adsorption
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: |
Stroppolo; Federico;
(Aldesago, CH) ; Ardalan; Shahbaz; (Maroggia,
CH) |
Correspondence
Address: |
ROTHWELL, FIGG, ERNST & MANBECK, P.C.
1425 K STREET, N.W.
SUITE 800
WASHINGTON
DC
20005
US
|
Assignee: |
ALPEX PHARMA S.A.
Mezzovico
CH
|
Family ID: |
37440618 |
Appl. No.: |
11/186925 |
Filed: |
July 22, 2005 |
Current U.S.
Class: |
424/10.2 ;
424/464; 514/282; 514/317 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 25/04 20180101; A61K 9/0056 20130101; A61K 47/18 20130101;
A61K 31/4468 20130101; A61P 23/00 20180101; A61K 9/2013
20130101 |
Class at
Publication: |
424/010.2 ;
424/464; 514/282; 514/317 |
International
Class: |
A61K 31/485 20070101
A61K031/485; A61K 9/44 20060101 A61K009/44; A61K 31/445 20060101
A61K031/445; A61K 9/20 20060101 A61K009/20 |
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.
Description
[0001] The present invention concerns solid dosage formulations of
narcotic drugs having improved buccal adsorption.
[0002] 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 INVENTION
[0003] Buccal 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 INVENTION
[0004] Surprisingly, 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.
[0005] 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%.
[0006] 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.
[0007] Examples of active components that may be advantageously
formulated in solid dosage form according to the invention
include:
[0008] 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.
[0009] The invention is illustrated by the following Examples:
EXAMPLE #1
Example #1A
[0010] Preparation of a Oral Dispersible Tablet Containing Amine
(Arginine)
[0011] Oral dispersible tablets containing 200 mcg of Fentanyl were
obtained as follows:
[0012] A) 1.05 g of Fentanyl and 50 g of PEG 600 were dissolved
into 90 g of purified water.
[0013] 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.
[0014] C) At the end of granulation and drying, 43.33 g of arginine
free base and 16.67 g of magnesium stearate were added.
[0015] D) The product was blended until homogeneity and compressed
in toroidal tablets having a diameter of 10 mm and weighing 300 mg
each
Example #1B
[0016] Preparation of an Oral Dispersable Tablet without Amine
(Arginine)
[0017] Oral dispersible tablets containing 400 mcg of Fentanyl have
been obtained as follows:
[0018] E) 2.1 g of Fentanyl and 50 g of PEG 600 was dissolved into
90 g of purified water.
[0019] 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.
[0020] G) The product was blended until homogeneity and compressed
in toroidal tablets having a diameter of 10 mm and weighing 300 mg
each
EXAMPLE # 2
[0021] A 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.
[0022] The results are reported in the following Table:
TABLE-US-00001 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
[0023] 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.
* * * * *