Proteinoid carriers and methods for preparation and use thereof

Details Proteinoid carriers and methods for preparation and use thereof Proteinoid carriers and methods for preparation and use thereof

1998-11-23

2002-07-02

Webman, Edward J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C514S773000, C514S952000

Reexamination Certificate

active

06413550

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to proteinoids and proteinoid carriers made from them. The proteinoid carriers releasably encapsulate active agents and have extended longer shelf life and/or photostability. Methods for the preparation of such proteinoid carriers are also disclosed.
BACKGROUND OF THE INVENTION
The available modes of delivery of pharmaceutical and therapeutic agents often are severely limited by chemical or physical barriers or both, which are imposed by the body. For example, oral delivery of many such agents would be the route of choice if not for the presence of chemical and physicochemical barriers such as extreme pH in the gut, exposure to powerful digestive enzymes, and impermeability of gastrointestinal membranes to the active ingredient. Among the numerous pharmacological agents which are known to be unsuitable for oral administration are biologically active peptides and proteins, such as insulin. These agents are rapidly destroyed in the gut by acid hydrolysis and/or by proteolytic enzymes.
A great deal of research has been devoted to developing effective oral drug delivery methods and systems for these vulnerable pharmacological agents. The proposed solutions have included:
(a) co-administration of adjuvants (such as resorcinols and non-ionic surfactants polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether to increase the permeability of the intestinal walls; and
(b) co-administration of enzymatic inhibitors, such as pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFF) and trasylol to avoid enzymatic degradation.
The use of such substances, in drug delivery systems, is limited however either because of:
(a) their inherent toxicity when employed at effective amounts;
(b) their failure to protect the active ingredient or promote its absorption;
(c) their adverse interaction with the drug.
Liposomes as drug delivery systems have also been described. They provide a layer of lipid around the encapsulated pharmacological agent. The use of liposomes containing heparin is disclosed in U.S. Pat. No. 4,239,754 and several studies have been directed to the use of liposomes containing insulin; e.g., Patel et al. (1976)
FEBS Letters
Vol. 62, page 60 and Hashimoto et al. (1979)
Endocrinol. Japan
, Vol. 26, page 337. The use of liposomes, however, is still in the development stage and there are continuing problems, including:
(a) poor stability;
(b) inadequate shelf life;
(c) limited to low MW (<30,000) cargoes;
(d) difficulty in manufacturing;
(e) adverse interactions with cargoes.
More recently, synthetic amino acid polymers or proteinoids, forming microspheres, have been described for encapsulating pharmaceuticals. For example, U.S. Pat. No. 4,925,673 (the '673 patent), the disclosure which is hereby incorporated by reference in its entirety, describes such microsphere constructs as well as methods for their preparation and use. The '673 patent also describes microspheres which encapsulate pharmaceutical agents for delivery into the gastrointestinal tract or into the blood.
While the proteinoid microspheres described in the ‘673 patent are useful for their intended purposes, the physicochemical properties of the proteinoid microspheres, such as light sensitivity, shelf life and the selectivity of their solubility in various portions of the gastrointestinal tract, could be improved. Additionally, there is a need in the art for microspheres that can encapsulate a broader range of active agents such as polar drugs.
The method employed in the '673 patent to prepare proteinoids produces a complex mixture of high molecular weight (MW) (>1000 daltons) and low MW (≦1000 daltons) peptide-like polymers which are difficult to separate. Moreover, the method produces a small amount of the low MW proteinoids which is the microsphere-forming fraction. Hence, an improved method of preparing of the proteinoids is also desired.
Accordingly, there is a need in the art for improved proteinoid carriers as well as improved methods for their preparation.
OBJECTS OF THE INVENTION
It is an object of this invention to provide proteinoids which forms proteinoid carriers as a delivery system with enhanced stability towards at least one of photodegradation and decomposition over time.
It is another object of the invention to provide a proteinoid that forms proteinoid carriers with more selective solubility under various conditions such as pH.
It is yet another object of the invention to provide proteinoid carriers encapsulating biologically active agents which are selectively releasable within particular portions of the gastrointestinal tract.
It is a further object of the invention to provide proteinoid carriers which promote the bioavailability of pharmaceutical agents which otherwise display poor absorption in the gastrointestinal tract.
It is yet a further object of the invention to provide an improved method for producing proteinoid carriers having particular characteristics and for improving yield of the desired proteinoid carriers.
It has been found that these objects and other advantages, which will be apparent from this specification, are achieved by the invention described below.
SUMMARY OF THE INVENTION
The present invention relates to improved proteinoid carriers and methods of making and use thereof.
Proteinoids of a MW ranging between about 250 and about 2400 daltons and of defined amino acids are useful in preparing proteinoid carriers with improved stability against photodegradation and/or decomposition. The proteinoids comprise a peptide polymer selected from the group consisting of:
(i) peptide polymers made from at least one first monomer selected from the group consisting of tyrosine and phenylalanine; and from at least one second monomer selected from the group consisting of glutamic acid, pyroglutamic acid, glutamine, and aspartic acid;
(ii) peptide polymers made from at least one first monomer selected from the group consisting of tyrosine and phenylalanine; and from at least one second monomer selected from the group consisting of glutamic acid, pyroglutamic acid, glutamine, and aspartic acid; and from at least one third monomer selected from the group consisting of lysine, arginine and ornithine, the proteinoid being a microsphere- and/or microcapsule-forming proteinoid and being soluble within a selected pH range.
The proteinoid molecules of the invention contain between about 2 and about 20 amino acid residues, preferably between about 2 and about 8 amino acid residues, and has a molecular weight which ranges between about 250 and about 2400 daltons, preferably between about 250 and about 600, and most preferably between about 250 and 400 daltons.
The proteinoid carriers are useful as delivery systems to releasably encapsulate and carry a broad range of cargoes including pharmaceutical agents, dye reagents and cosmetic ingredients. In particular, the proteinoid carriers are useful as oral delivery systems of sensitive pharmaceutical agents, which normally would not be administrable via the oral route, for selective release at targeted regions of the gastrointestinal tract.


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