Intranasal administration of polypeptides in powdered form

Details Intranasal administration of polypeptides in powdered form Intranasal administration of polypeptides in powdered form

2002-12-23

2004-11-09

Page, Thurman K. (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C424S400000, C424S489000, C424S499000, C514S002600, C514S012200, C514S023000

Reexamination Certificate

active

06815424

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention concerns pharmaceutical compositions for the intranasal administration of a biologically active polypeptide in powder form, and a method of administering such compositions. More specifically, the invention relates to pharmaceutical compositions for the intranasal administration of a therapeutically effective amount of a biologically active polypeptide, especially an LHRH analogue, in powder form suitable for intranasal administration; and to a method of administering such compositions. The intranasal compositions and methods of this invention provide effective systemic administration of therapeutically effective amounts of biologically active polypeptides, particularly in high doses.
The traditional and most widely used method of administration of therapeutic agents is by the oral route. However, in the case of polypeptides, such delivery is not feasible due to several factors, for example because of the hydrolysis of the peptides by digestive enzymes or because polypeptides are absorbed very poorly or not at all from the gastrointestinal tract. The methods most commonly used for administration of polypeptide therapeutic agents are by repeated injection, intramuscular (IM), subcutaneous (SC) or intravenous (IV) infusion. These methods are acceptable in situations where a very limited number of injections are required, or in treating life-threatening diseases, but are undesirable for chronic administration. However, the nature of many of the diseases, disorders and conditions susceptible to improvement by polypeptide administration is chronic rather than acute, thus necessitating frequent injections over a prolonged period of time. There is, therefore, a need for an efficacious and economical delivery system for polypeptide agents.
The present invention is particularly useful for the chronic administration of luteinizing hormone-releasing hormone (LHRH) analogues. The natural LHRH peptide is a decapeptide comprised of naturally occuring amino acids (which have the L-configuration except for the achiral amino acid glycine). Its sequence is as follows: (pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2
. Many analogues of this natural material have been studied. Continuous chronic administration of LHRH agonist and antagonist analogues has been found to block the secretion of gonadotropins in both male and female animals, thereby suppressing the production of gonadal steroids and gametes. As a result, such LHRH analogues have been indicated for controlling fertility, suppressing sexual behaviour in animals, causing regression of endometriotic lesions and prostatic cancers, and in the treatment of precocious puberty and the gynecological diseases. Several methods have been proposed for the systemic delivery of LHRH analogues, but none of the methods are regarded as ideal.
As with most polypeptides, oral administration of LHRH analogues is extremely inefficient because they are inactivated or not absorbed in the gastrointestinal tract. Conventional administration of LHRH analogues includes subcutaneous and intramuscular injections. However, because LHRH analogues have short circulatory half-lives ranging from several seconds to a few hours, frequent injections are necessary to achieve effective therapeusis, rendering chronic administration difficult, inconvenient and costly.
Another approach for chronic administration of polypeptides including the LHRH analogues is the implantation or other in situ application of long acting controlled release systems. However, the implementation of such systems requires the device to be implanted and possibly to be removed surgically if interruption of treatment becomes necessary. A more broadly useful approach would be the intranasal administration of polypeptides, thus providing effective systemic administration of therapeutically effective amounts of the polypeptide without the necessity of daily or more frequent injections, or the cost and inconvenience of surgery.
The ability of certain polypeptides to be intranasally absorbed into the systemic system from nasally administered solutions in which the polypeptide is dissolved is known.
U.S. Pat. No. 4,476,116 discloses a nasal spray composition comprising an LHRH analogue and a chelating agent in an aqueous solution. The solution gave enhanced absorption compared to nasal solutions with no chelating agent.
Hirai,
Diabetes,
27, p 296-299 (1978), discloses the nasal administration of insulin as a solution, optionally containing a surfactant, for example sodium glycholate.
However, conventional practice indicates that aqueous solutions of polypeptides provide poor bioavailability and relatively high inter-subject variability when administered nasally. Vickery et al. have disclosed intranasal administration of nafarelin acetate in aqueous solution (Transnasal Systemic Medications, ed. Y. W. Chien, Piscataway, N.J. 1985). However, the low aqueous solubility of nafarelin acetate (about 2 mg/ml in saline solution) restricts the usefulness of this approach, as in the case where a high dose of nafarelin acetate is needed to be therapeutically useful it is not possible to dissolve the required amount of nafarelin acetate in the limited amount of aqueous solution which may be introduced into the nose (about 100 &mgr;l for each nostril). Thus, in the case of nafarelin acetate, the upper dosage achievable from nasal solution is about 400 &mgr;g. As transport across the nasal membranes from such a solution is very limited, (giving about 2% bioavailability compared to injection), the total amount of nafarelin entering the bloodstream is only about 8 &mgr;g per dose.
Another disadvantage of using an aqueous solution for intranasal formulations is that polypeptides in general are less chemically stable in solution than as a solid, thus limiting the useful shelf life. Aqueous solutions also require the addition of an agent to kill microorganisms or inhibit their growth. Such agents may cause damage to nasal mucosa.
Powdered forms of polypeptides have also been intranasally administered. However, these compositions have typically required the presence of a quarternary ammonium salt, starches, sugars, water-absorbing gum, polymer, cellulose derivative or a cyclodextrin. All of these excipients have a disadvantage with regard to nasal administration. The quarternary ammonium salt and the low molecular weight water-soluble saccharides and polysaccharides generate an osmotic pressure which impedes absorption of the polypeptide by pulling water out of the nasal membranes in the opposite direction of the intended absorption. Cellulose derivatives and water absorbing/water insoluble excipients swell in the nasal membrane and present an additional layer of resistance to absorption. They also pull water out of the nasal membrane. Cyclodextrins decrease absorption by complexing with hydrophobic groups in the polypeptide. Cyclodextrins are not accepted in the World Pharmacopoeias.
European Patent Application 193,372 discloses a powdery composition for intranasal administration of polypeptides, such as calcitonin and insulin. Required in the composition is a quarternary ammonium salt and a lower alkyl ether of cellulose.
European Patent Application 122,036 discloses a formulation for powdered peptides, including LHRH, suitable for nasal administration. The formulation includes, as a required ingredient, a water-absorbing/water-insoluble base such as a starch, protein, gum or a cross-linked polymer such as polyvinylpyrrolidone, optionally in the presence of an excipient such as mannitol, sorbitol, aminoacetic acid, sodium chloride, phospholipids, etc.
Nagai,
J. Controlled Release,
1, p 15-22 (1984) discloses a powder formulation of insulin, optionally with an excipient, for example lactose, cellulose, hydroxypropyl cellulose or carbopol 934, for nasal administration.
European Patent Application 094,157 discloses a composition comprising a highly hydrophilic drug, such as a polypeptide, polysaccharide, aminoglycoside, beta lactam antibiotic, nucleic acid, etc, in combination with

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