Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Coated – impregnated – or colloidal particulate
Reexamination Certificate
1997-03-11
2002-08-13
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Coated, impregnated, or colloidal particulate
C424S489000, C424S495000, C424S499000, C424S501000, C424S009400
Reexamination Certificate
active
06432381
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to improved formulations of poorly soluble crystalline therapeutic agents which are absorbed through mucous membranes.
2. Background of the Invention
There is a constant need in the pharmaceutical industry for improved pharmaceutical formations which enhance the efficacy of poorly soluble therapeutic agents. There is especially a need for formulations that (1) enhance the adsorption of poorly soluble therapeutic agents across mucous membranes or (2) extend the period of time that poorly soluble therapeutic agents useful for treating of a site have contact with the mucosa of the site.
Since most poorly soluble crystalline therapeutic agents do not inherently adhere to mucosal surfaces, there is a need to provide in such formulations, primary surface active stabilizers with appropriate mucoadhesive properties and secondary excipients that provide for an improvement in therapeutic efficacy as compared with existing products and formulations. Therefore, the physical-chemical properties of the therapeutic agents, and any desired surface active stabilizers and viscosity modifiers must be taken into consideration.
The identification of surface active stabilizers for use with small particles of crystaline poorly soluble drugs, wherein the surface active stabilizer has bioadhesive or mucoadhesive properties to mucous membranes, in particular, to the entire GI tract, has not been reported to date. The development of appropriate surface active stabilizers that will enable mucous membranes to be utilized to enhance bioavailability represents a difficult technical problem.
Bioadhesion is usually achieved by interaction of either a synthetic or natural polymeric substance with mucosal membranes. Such technology has been employed to enhance drug delivery by decreasing the transit time of a drug substance in the GI tract and hence promote an opportunity for enhanced absorption. Highly charged carboxylated polyanions are good candidates for use as bioadhesives in the GI tract. See, for example: Park, K. and Robinson, J. R., Bioadhesion: Polymers and Platforms for Oral-Controlled Drug Delivery; Method to Study Bioadhesion. Int. J. Pharm., 19, 107 (1984). The formation of a bioadhesive bond between a polymeric substance and the mucosal lining of the GI tract can be visualized as a two step process, i.e., initial contact between the two surfaces and the formation of secondary bonds due to non-covalent interactions. Bioadhesives specific for mucous membranes must interact with the mucus layer during attachment. Mucus, a general term for the heterogenous secretion found on the epithelial or endothelial surfaces of the mucous membranea, is made of the following components: glycoprotein macromolecules, inorganic salts, proteins, lipids and mucopolysaccharides. These glycoproteins typically consist of a protein core with carbohydrate side chains. This forms a network of mucus that is a continuous layer covering the muscous membrane. From a bioadhesive perspective, mucus consists of highly hydrated, crosslinked linear, flexible yet random coiled glycoprotein molecules with a net negative charge. Understanding the principles of bioadhesion is the basis for producing an improved formulation for poorly soluble therapeutic agent. Bioadhesion accounts for the interaction between a biological surface and a biomaterial substance. As noted previously, bioadhesive agents are usually polymeric substances that adhere to tissues by ionic or covalent bonds or by physical attachment. Several theories of bioadhesion have been published including electronic, adsorption, wetting, diffusion and fracture theories. Bioadhesives bind to membrane surfaces and are retained for variable periods of time.
The primary difficulty with previously reported mucoadhesive stabilizers is that they do not interact effectively with both the particles of the therapeutic agent and mucous membrane uniformly so that, e.g., both the upper and lower GI tract can be used as sites to increase bioavailability. The stabilizers used for this purpose must be adsorb sufficiently to the different regions of the GI tract. In practice, stabilizers tend to be adsorbed at some biological surfaces differentially than at others due to a variety of complex reasons. There is a need for formulations of particles of therapeutic agents that are adsorbed sufficiently over the entire mucous membrane.
It has now been discovered that particles of crystalline therapeutic agents modified by having a poloxamer absorbed on the surface thereof, can be adsorbed onto the mucosal surface, including the GI tract.
In another embodiment the present invention relates to improved formulations of therapeutic agents, including gastrointestinal therapeutic agents, wherein the formulations provide prolonged local contact of the therapeutic agents with the mucosal layer, including the gastrointestinal tract.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a therapeutic composition comprising:
from about 0.1% to about 45% w/v, and, preferably, from about 0.5% to about 15% w/v, of particles of a poorly water-soluble crystalline therapeutic agent having a weight average particle size of less than about 2,000 nm, more preferably, a weight average particle size of less than about 1,000 nm, and most preferably, a weight average particle size of less than about 400 nm;
from about 0.1% to about 10% w/v, and preferably of from about 0.25% to about 5% w/v of a poloxamer; and
water to make 100% w/v.
These compositions can be administered by any route that will result in the therapeeutic agent having contact with a mucous membrane. These routes include oral, rectal, nasal, occular, inhalation and vaginal. Preferred is oral and rectal because the compositions of the present invention will enable the thereapeutic agent to be adsorded across the mucous mebrane of the entire GI tract resulting in greatly enhance adsorption.
Secondary stabilizers may also be used in the therapeutic composition up to about 1% w/v, preferably up to about 0.2% w/v, and most preferably up to about 0.1% w/v. Secondary stabilizers include dioctylsulfosuccinate (DOSS) and sodium lauryl sulfate (SLS).
Other ingredients customarily used in pharmaceutical formulations may also be included, such as flavorants, colorants and preservatives to provide pharmaceutically acceptable and palatable formulations.
The poloxamers useful in the present invention have an average molecular weight of from about 1,000 to 15,000 daltons; preferred have an average molecular weight of about 5,000 to 15,000 daltons.
Poloxamers are polyethylene-polypropylene glycol block polymers containing ethylene oxide (PEO) and propylene oxide (PPO) moles according to the formula
(PEO)
a
−(PPO)
b
−(PEO)
c
.
Preferred are poloxamers wherein;
a is 46 to 128;
b is 16 to 67; and
c is 46 to 128.
More preferred are poloxamers wherein;
a is 46, 52, 62, 75, 97, 98, 122 and 128;
b is 16, 30, 35, 39, 47, 54 and 67; and
c is 46, 52, 62, 75, 97, 98, 122 and 128.
Table 1 shows the various poloxamers by manufacturer-designated number.
TABLE 1
Molecular Weights of Poloxamers
Av. Values
Poloxamer No.
Pluronic
Av. Mol. Wt
a
b
c
401
4,400
6
67
6
402
5,000
13
67
13
403
5,750
21
67
21
407
F127
12,000
98
67
98
331
3,800
7
54
7
333
4,950
20
54
20
334
5,850
31
54
31
335
6,000
38
54
38
338
F108
15,000
128
54
128
282
3,650
10
47
10
284
4,600
21
47
21
288
F98
13,500
122
47
122
231
2,750
6
39
6
234
4,200
22
39
22
235
4,600
27
39
27
237
F87
7,700
62
39
62
238
F88
10,800
97
39
97
212
2,750
8
35
8
215
4,150
24
35
24
217
F77
6,600
52
35
52
181
2,000
3
30
3
182
2,500
8
30
8
183
2,650
10
30
10
184
2,900
13
30
13
185
3,400
19
30
19
188
F68
8,350
75
30
75
122
1,630
5
21
5
123
1,850
7
21
7
124
2,200
11
21
11
101
1,100
2
16
2
105
1,900
11
16
11
108
F38
5,000
46
16
46
Certain number of these poloxamers are also known as P
Eickhoff W. Mark
Illig Kathleen J.
Liversidge Gary G.
Ruddy Stephen B.
Sarpotdar Pramod
Elan Pharma International Limited
Foley & Lardner
Hartley Michael G.
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