Solid pharmaceutical formulation containing lovastatin and...

Details Solid pharmaceutical formulation containing lovastatin and... Solid pharmaceutical formulation containing lovastatin and...

2000-09-08

2004-02-24

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S460000, C424S474000, C424S489000, C424S451000

Reexamination Certificate

active

06696086

ABSTRACT:

The present application claims priority from Slovenian Patent Application no. P-9900211, entitled “TRDNA FARMACEVTSKA FORMULACUA, KI VSEBUJE LOVASTATIN AND SIMVASTATIN, IN NJENA PRIPRAVA,” filed September 10, 1999, which application is incorporated herein by reference.
TECHNICAL FIELD
Lovastatin and simvastatin are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic and hypolipidemic agents. Lovastatin is produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus or Monascus, and simvastatin is the product of lovastatin obtained by the methods of chemical synthesis.
The present invention relates to a novel solid pharmaceutical formulation containing lovastatin and simvastatin, respectively, which ensures rapid dissolution of the active substance from the pharmaceutical formulation. The present invention also relates to the process for its preparation.
The present invention also relates to the methods for the production of lovastatin and simvastatin with suitable physical and chemical properties for preparation of the pharmaceutical formulation of the current invention.
Simvastatin and lovastatin are lipophilic molecules of very poor solubility in water. The partition coefficient between octanol and water for lovastatin is about 20 000, for simvastatin about 50 000, which is similar to that of griseofulvin, an antibiotic with well-known dissolution problems. The poor solubility is also suggested by data that at room temperature the volumes of water required to dissolve 20 mg of lovastatin and simvastatin are about 15 liters and 14 liters, respectively, in contrast to equal amounts of fluvastatin and pravastatin, the statin analogs, which dissolve in 10 ml and only 0.07 ml of water, respectively.
The absorption of an active substance in the body following oral administration of a pharmaceutical formulation, particularly from the small and large intestine, is affected primarily by dose size/dissolution rate ratio, dissolution rate, degradation and metabolic conversion in the lumen and effective permeability absorption of an active substance across the intestinal mucosa. The results of the experiments have shown that lovastatin and simvastatin are relatively stable in the intestinal fluid; however, due to their strong lipophilic nature, passage of lovastatin and simvastatin from the small intestine across the intestinal mucosa into the bloodstream is a more serious problem. Lovastatin and simvastatin cross the intestinal mucosa primarily by passive transport (diffusion), and to a smaller extent by active transport (it was suggested from some studies that ATP-dependent transport proteins involved in the transport mechanism in the apical membrane of erythrocytes may recognise lovastatin as a substrate). Apart from the chemical properties of the substance, the rate and extent of passive transport depends primarily on a concentration gradient restored at the intestinal mucosa—higher concentration gradients suggest a more rapid passage of an active substance from the gastrointestinal tract into the body. In spite of the fact that in general, lipophilic substances cross the cellular membranes more easily than hydrophilic substances, it has been shown that the diffusion rate across the membrane in case of more lipophilic substances (partition coefficient octanol/water>1000) was lower than in case of less lipophilic substances (partition coefficient octanol/water<100). One of explanations is an association that at diffusion through the membrane association of the lipophilic substance with membrane lipids occurring at crossing the membrane, which delays passage across membranes.
In case of substances of poor solubility and strong lipophilic character, which cross the membrane only by passive diffusion, dissolution rate of a substance from a particular pharmaceutical formulation is one of the key factors which define the rate and the extent of absorption. The faster a substance dissolves, the higher local concentrations of the substance are, resulting in more rapid passage across the membrane. Relevance of producing high local concentrations of lovastatin and simvastatin has clearly been shown in the tests with extended-release pharmaceutical formulations where the bioavailability of both substances was almost by 50% lower than with immediate-release standard tablets. Lower bioavailability is due to lower local concentrations of the active substance resulting in a smaller flux of the active substance through the intestinal membrane. Measurements of the intestinal membrane absorption following oral lovastatin have shown that only 31% of a total dose crosses the membrane (in case of simvastatin between 60 and 80%) and in spite of a relatively long absorption phase (an active form of lovastatin reaches peak concentration in blood 2.8 hours post-dose), lovastatin has a very low bioavailability primarily due to poor absorption.
Regarding great relevance of sufficiently rapid dissolution of lovastatin and simvastatin from a particular pharmaceutical formulation, for an effective pharmaceutical formulation it is of particular importance that the active substance in the region where drug absorption occurs undergoes rapid dissolution and obtains the highest possible concentration gradient over the shortest possible time. After rapid dissolution of lovastatin and simvastatin, respectively, transport rate of an active substance across the membrane is indirectly greater thereby the effective absorption of an active substance from the alimentary tract is also indirectly increased. The above described facts impose the problem to pharmaceutical technologists how to prepare a pharmaceutical formulation which will facilitate the most efficient absorption of a strongly lipophilic in water poorly miscible active substance.
In our work we have surprisingly found that a size and specific surface area of crystals—particles used for the preparation of a pharmaceutical formulation are the parameters which have an impact on the dissolution rate of lovastatin and simvastatin, respectively from a particular pharmaceutical formulation. Thus, we have found that the bioavailability improved when lovastatin crystals and simvastatin crystals, respectively, with a smaller particle size and a larger specific surface area, are used for the preparation of a particular pharmaceutical formulation. We have noticed that dissolution rate of the active substance from a particular pharmaceutical-formulation was markedly higher if a substance with a smaller particle size and a larger specific surface area was used than when a substance with large size particles and a smaller specific area was used.
The results of our investigations have shown that for the preparation of a pharmaceutical formulation of the present invention, it is advantageous to use lovastatin and simvastatin, respectively, with a particle size D(0.9) between 15 and 100 &mgr;m (D(0.9) denotes a particle size wherein 90% (volume) particles in the substance used are below D(0.9)) and a specific particle surface area between 1 and 4 m
2
/g measured by the BET method (S. Brauner: The Adsorption of Gases and Vapours, Princeton, (1945)).
To illustrated the advantage of using lovastatin and simvastatin, respectively, with a smaller particle size and a large specific surface area, we have made two sets of tests. At first we have prepared three samples of lovastatin* with varying particle size and compared dissolution** of those samples in water (Table I).
Time
A
B
C
(min)
(mg/l)
(mg/l)
(mg/l)
0
0
0
0
1
0.65
0.50
0.25
3
0.77
0.68
0.30
5
0.78
0.71
0.40
10
0.81
0.78
0.56
30
0.88
0.87
0.82
50
0.90
0.95
0.94
*=physical parameters of lovastatin samples
d (0.1)
d (0.5)
d (0.9)
Spec. Pov.
&mgr;m
&mgr;m
&mgr;m
m
2
/g
A
1.6
6
22
3.3
B
1.4
7.9
31
2.2
C
17
54
163
0.7
**−200 mg of lovastatin sample suspended in 0.1% aqueous solution of Tween 80 (necessary for dispersion of sample) was stirred for 120 min on magnetic stirrer. After that the sample was diluted 100 times and the concentrati

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