Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-09-21
2002-03-05
Moezie, F. T. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S773000, C514S774000, C424S422000, C424S426000, C424S457000, C424S458000
Reexamination Certificate
active
06352974
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel compositions, in particular to compositions comprising calcitonin or a fragment or conjugate thereof and to methods for preparing such compositions. It also relates to oral formulations comprising the compositions and to shelf stable calcitonin or a fragment or conjugate thereof.
Many proteins and polypeptides have potential as pharmaceutical agents but because they are susceptible to both physical and chemical degradation they are often too unstable to be included in pharmaceutical formulations. In particular such proteins and polypeptides do not have adequate shelf life.
The primary, secondary and tertiary structures of proteins and polypeptides are all vulnerable to various types of disruption. Some proteins and peptides are physically unstable as a result of, for example, adsorption, aggregation or denaturation. Others are chemically unstable as a result of, for example, oxidation, hydrolysis, deamidation, beta-elimination, racemisation or disulphide exchange (if the polypeptide contains a disulphide bridge e.g. a cystine link). Many proteins and polypeptides are susceptible to a number of these factors.
In order to formulate proteins and polypeptides into pharmaceutical preparations the factors described above must be taken into consideration. Thus proteins and peptides often have more complex formulation requirements than chemical pharmaceuticals. This is further complicated by the fact that many stages in the processing of pharmaceutical formulations introduce further stresses on the proteins and polypeptides which destabilise them. For example, processes such as heating, shaking, freeze thawing and processes in which the proteins or polypeptides are exposed to hydrophobic surfaces or to moisture may induce aggregation of the protein or polypeptide. Aggregation may also occur during the storage of the formulation, particularly if it is exposed to moisture.
Various excipients such as albumin, amino acids, sugars, chelating agents, cyclodextrins and polyhydric alcohols, have been added to proteins and polypeptide pharmaceutical formulations in order to increase their stability. These have been of varying success depending on the protein or polypeptide concerned. The excipients stabilise the proteins and polypeptides in different ways, not all of which are fully understood, for example, albumin is added to prevent surface adsorption of pharmaceuticals by preferentially adsorbing to surfaces, whilst amino acids are added to reduce surface adsorption, to inhibit aggregation or to reduce heat degradation. Sugars are added to provide stability during processes such as heating and lyophilisation.
BACKGROUND OF THE INVENTION
Although the use of excipients to stabilise proteins and polypeptides has proved suitable for the stabilisation of some proteins and polypeptides it is inadequate for the stabilisation of less stable proteins and polypeptides, particularly those containing a disulphide bridge, such as a cystine link, e.g. calcitonin. There is therefore a need for further methods of stabilising proteins and polypeptides which are capable of stabilising these less stable proteins and polypeptides. In particular there is a need for a method of stabilising polypeptides with a disulphide bridge, e.g. calcitonin. The present invention utilises the techniques of freeze drying to provide such a method.
Proteins and polypeptides have previously been lyophilised (e.g. by freeze drying) in order to prepare powders which may be stored and reconstituted when required. The proteins and polypeptides are freeze dried in the presence of cryoprotectants and lyoprotectants (e.g. sugars, polyols, polymers such as polyethylene glycol, amino acids and organic salts such as sodium acetate) which are required to prevent the denaturation of the protein or polypeptide.
This technique is not suitable for all proteins and polypeptides, in some cases the cryoprotectants and lyoprotectants induce conformational instability to the proteins or polypeptides to be lyophilised or the freeze dried product has been found to be susceptible to degradation.
Thus, some proteins and polypeptides have been freeze dried in the presence of cryoprotectants and lyoprotectants but these techniques have not before been utilised to prepare solid oral preparations of unstable proteins or polypeptides such as those having a disulphide bridge. In particular these techniques have not before been utilised to provide a stable oral formulation of calcitonins. Furthermore, the known techniques relate only to the stabilisation of aqueous preparations of proteins and polypeptides to provide injectable or nasal dosage forms and do not provide solid dosage forms.
Calcitonins are hypocalcemic hormones found in the thyroid, parathyroid and thymus glands of man and in separate organs called ultimobranchial bodies in non-mammalian vertebrates. During hypercalcemia calcitonins reduce elevated plasma calcium concentration to normal levels by inhibiting bone resorption. Calcitonins are therefore used to treat a variety of conditions such as Paget's disease, post menopausal osteoporosis and also to treat hypocalcemia resulting from vitamin D intoxication, neoplastic disease, thyrotoxicosis or hyperthyroidism.
Salmon calcitonin is a polypeptide with a molecular weight of 3431.9 which consists of 32 amino acids. It has a disulphide bridge (cystine link) between the first and seventh amino acids at the amino end of the polypeptide chain, which is essential for its biological activity, and a prolinamide group at the carboxyl terminal amino acid. The presence of this disulphide bridge contributes to the lack of stability of calcitonin because, under thermal stress, it is susceptible to beta-elimination to produce free thiols. These thiols render the molecule vulnerable to degradation via various pathways and may also increase the occurrence disulphide interchanges thus affecting the conformation and therefore the activity of the polypeptide.
Calcitonins are currently only available in solution and are administered by intravenous infusion, by intramuscular injection, subcutaneously or intranasally. In order to maintain biological activity pharmaceutical preparations containing calcitonin must be stored at a temperature of 2 to 8° C. Storage at low temperatures slowing down the extent of degradation which occurs at a high rate in the liquid phase.
It is widely recognised in the pharmaceutical industry that oral drug delivery is the preferred mode of drug administration. Whether the pharmaceutical is administered by the patient or by a medical practitioner oral administration is simpler than invasive methods of administration. Oral administration is generally more acceptable to patients and so increases patient compliance. Oral administration also avoids the need to use sterilised equipment such as syringes when administering the pharmaceutical, which results in increased safety for the patient.
The preparation of solid pharmaceuticals is simpler and cheaper than the preparation of pharmaceuticals in the form of a solution. This is particularly the case where the solution is an injectable solution or an internasal spray. In contrast to oral pharmaceutical formulations injectable pharmaceutical solutions must be prepared in sterile conditions in highly regulated laboratories. This is necessary because pharmaceuticals administered by injection are delivered directly into the blood stream or the muscles of the patient, so even a small amount of contamination could cause significant adverse effects. Pharmaceuticals which are administered in solid oral dosage forms are ingested and pass through the alimentary canal before the active component is released into the blood stream or into the tissues of the patient. Thus small amounts of contamination will be excreted by the body during the normal digestive process. The requirement to prepare pharmaceutical solutions under highly sterile conditions increases the cost and inconvenience of their preparation.
Although solid oral dosage forms are d
Ghirri Matteo
Zema Marco
Eurand International S.p.A.
Moezie F. T.
Thompson Hine LLP
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