The advancement in the field of medicine has improved the quality of life and increased the life expectancy of humans. However, there is a limit to the efficacy of a single pharmaceutically active ingredient in treating patients with medical disorders. Thus, it is common to administer multiple medications having different mechanisms (modes) of action simultaneously or sequentially for synergistic effects. For instance, the risk factors of such a chronic cardiovascular disease as hypertension and the like are well-known, yet most patients are treated with medications due to the difficulties in their risk factor management. It is also difficult to treat them owing to their low compliance to taking medicine. In case where consistent and incessant use of medications seems inevitable, it is advised to use multiple medications having different mechanisms of action so as to provide effective prevention and treatment, as well as to reduce potential undesirable side effects, which may attribute to the long-term use of a single drug. According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7), it is recommended to use multiple medications having different mechanisms of action in case where administration of a single drug has failed to effectively control blood pressure.
However, administration of two or more separate drugs may reduce patents' compliance to taking medicine, causing great inconvenience to the patients who are subjected to continuous drug treatments. Further, the patients normally have to carry such separate drugs with them. It will also give the patients great inconvenience in their daily lives.
In order to redress such problems, there has been suggested a method of packaging a number of medications in a single package. For instance, Torrent Pharmaceuticals Ltd. (India) has released a composite formulation “CVpill,” a single kit containing a capsule and a tablet for treating a cardiovascular disease. CVpill consists of a capsule containing 10 mg of Atorvastatin in powder form, Ramipril in powder form and 75 mg of an enteric-coated aspirin tablet, and a tablet containing 50 mg of sustained-release Metoprolol. The capsule and the tablet must be administered once a day simultaneously. But such co-packaged products consisting of a simple kit can hardly improve patients' compliance to taking medicine, which, however, may be expected in a composite formulation. Therefore, there is a growing demand for a research on development of a “combination drug or composite formulation” of specific active ingredients.
The term “composite formulation,” as used herein, refers to a combination of two or more different active ingredients or drugs in a single unit dose such as tablet or capsule. However, development of a composite formulation for specific active ingredients is sometimes very difficult for the following reasons.
First, the combination of specific active ingredients to be used for a composite formulation should readily be made. Further, the composition comprising active ingredients and a pharmaceutically acceptable excipient should be in appropriate size and weight for administration thereof. However, it is not always easy to develop such composite formulations. If the amount of drugs to be employed is excessive or insufficient, it would be difficult to adjust the weight of the composition to an appropriate level. Also, unexpected problems may be encountered in the course of dealing with the various conditions resulting from the pharmacokinetical and pharmaceutical properties of the drugs.
Second, the chemical interactions between the active ingredients in the preparation of a composite formulation may reduce the stability of drugs. Especially, it is even more difficult to develop a fixed combination dosage form with sufficient physicochemical stability for a combination of drugs if the stability thereof may be reduced due to their chemical interaction when combined.
When a composite formulation of tablet is prepared, a double-layer or a triple-layer tabletting machine can be used to separate the active ingredients. However, not only does such method require special equipments, but it is also mechanically impossible to completely separate the main ingredients in each layer since an undesirable reaction may take place at the interface of the layers.
For a capsule, a conventional hard capsule is charged with drugs in the form of powder, granule or pellet. Conventionally, only a single active ingredient is generally charged in a hard capsule by a single charging step. Also, a drug in the form of powder, granule or pellet has a density lower than that of a tablet since the former is not subjected to a high pressure compressing step. Thus, there exists a limit in the amount of drugs in the form of powder, granule or pellet to be charged in a capsule. In order to charge a high dose of a main ingredient or more than one active ingredient in a single hard capsule, the size of capsule must be increased to accommodate such change. The weight of drugs to be charged in a hard capsule is proportional to the internal volume of the hard capsule, particularly the volume of the capsule body. The internal volume varies with the size of hard capsules: No. 00 (0.95 mL), No. 0 (0.68 mL), No. 1 (0.47 mL), No. 2 (0.37 mL), No. 3 (0.27 mL), and No. 4 (0.20 mL) (see Suheung Capsule homepage). If the size of the capsule becomes too big for accommodating a large amount of drugs, it may cause swallowing difficulties, e.g., dysphagia. Particularly, capsules having large sizes of No. 00 (8.5 mm in capsule cap diameter and 23.3 mm in capsule length) and No. 0 (7.6 mm in capsule cap diameter and 21.7 mm in capsule length) may cause difficulties for elderly people or children to swallow them. It may also be inconvenient to carry them due to their large size.
Therefore, the present inventors have endeavored to resolve the disadvantages of a composite formulation and developed a composite formulation comprising a tablet encapsulated in a hard capsule and having a shape conforming to the capsule body.