JPH09309843A - Preparation for trans-lung administration containing hyaluronic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject preparation for trans-lung administration, in which peptidic drugs are formulated with hyaluronic acid and by which the absorption of the peptidic drugs, particularly insulin, into the body system is significantly increased and the drugs are stabilized. SOLUTION: This method for preparation is carried out by dissolving an peptidic drug (e.g. human insulin or the like) into an isotonic phosphoric acid buffer brine (pH7.0) to prepare an aqueous solution of the peptidic drug and then by dissolving sodium hyaluronate into this aqueous solution, so that the solution finally becomes in a concentration of 0.075-0.125wt.%, to form an objective preparation for trans-lung administration, by which a dosage form capable of significantly increasing absorption of the peptidic drug, particularly insulin, into the body system is given and the drug in the preparation can be stabilized.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel dosage form of peptide drugs. More specifically, the present invention relates to a pharmaceutical preparation comprising a combination of a peptide drug and hyaluronic acid.

[0002]

2. Description of the Related Art Drugs with remarkable first-pass effect in the liver,
In general, peptide drugs that are easily absorbed by the digestive tract and hardly absorbed are usually administered by injection (intravenous or subcutaneous). However, injection administration generally causes patient distress and requires the assistance of certain practitioners.

Therefore, as a dosage form of the peptide drug having the above-mentioned characteristics, a dosage form through mucous membranes such as nasal mucosa, oral mucosa, lungs and vagina is being studied. And, for example, in the nasal mucosal dosage form, considerable results have been obtained regarding systemic absorption of the drug (eg, Japanese Patent Laid-Open No. Hei 3).
-246233 publication). In addition, since the absorption area is wide, for example, transpulmonary administration of insulin powder has been attempted. Furthermore, in order to enhance the absorption efficiency of the drug by the transmucosal dosage form, the combination of a specific surfactant or the p of the drug solution is used.
Regulation of H (reduction in pH generally enhances drug absorption efficiency) is also being investigated.

However, low pH can adversely affect the storage stability of the drug. In addition, it is often difficult to form an ideal mist when administered as an inhalant or a spray, such as transpulmonary administration, and there is a problem that drug utilization efficiency decreases. was there. On the other hand, the nasal mucosal dosage form described in JP-A-3-246233 solves the above-mentioned problems to some extent, but does not always absorb the drug as compared with the corresponding injection dosage form. I am not satisfied with the efficiency.

[0005]

Accordingly, it is an object of the present invention to provide a dosage form which exhibits drug absorption behavior comparable to that of an injectable dosage form.

[0006]

Means for Solving the Problems Conventionally, it has been used as a sustained-release polymer matrix for drugs (see, for example, JP-A-2-213, JP-A-5-97794 and JP-A-5-186362). And the above-mentioned JP-A-3-
As described in Japanese Patent No. 246233, hyaluronic acid, which is also considered to be used as a carrier for nasal mucosal dosage forms, is used in combination with a peptide drug as a certain aqueous solution in a pulmonary administration. It has been found here that it exhibits extremely excellent properties (stability and high absorption efficiency).

Therefore, according to the present invention, there is provided a preparation for pulmonary administration, which comprises a combination of a peptide drug and hyaluronic acid.

The peptide-based drug according to the present invention may be any peptide or protein that can be used as a medicine as long as it is in accordance with the object of the present invention. Peptide hormones, as well as their analogs are mentioned. The term “analog” as used herein includes in vivo precursors and derivatives that are active as hormones as exemplified in vivo.

Peptide drugs which can be preferably used in the preparation of the present invention include, but are not limited to, insulins and calcitonin among the above. The drug of the present invention can enhance the in vivo absorption efficiency of these drugs. The terms “insulins” and “calcitonins” are used as a concept including precursors and the like that can exhibit the respective activities in the living body as described above. However, particularly preferably used peptide drugs are insulin itself and calcitonin itself.

Another essential ingredient in the preparation of the present invention is hyaluronic acid. Hyaluronic acid may be of animal or microbial origin, with a molecular weight greater than about 850,000. Specifically, about 850,000-
Hyaluronic acid with a molecular weight of 2.2 million can be used.

In the present invention, the peptide drug and hyaluronic acid are used in combination. Such combinations may be in solid form for dissolution or suspension in an aqueous solution at the time of use, but are preferably in the form of an aqueous suspension or solution. According to the present invention, the stability of the drug itself is generally enhanced even in such a solution state and at a pH of 3.5 to 7.5. However, from the viewpoint of storage stability, the pH is preferably about 6.5 to about 7.5.

[0012] For example, insulin and calcitonin show excellent drug absorption in a polymer-free solution having a low pH value (for example, around 4), but according to the formulation of the present invention, the above-mentioned pH of about 6.5 to about At 7.5, a better bioabsorption of the drug is observed than in the polymer-free solution at pH 4. For particularly good absorption, the concentration of hyaluronic acid should be 0.075 to 0.125% by weight, in particular about 0.1% by weight, based on the total formulation weight.

These aqueous solutions may contain other organic substances (solvents, inhibitors, etc.) as long as the object of the present invention is met, but usually only physiological saline containing a buffer if necessary. It is preferable to prepare. The hyaluronic acid used in the aqueous solution may be either a free acid or a salt form of its alkali metal (sodium, potassium, etc.), and if necessary, a buffer is used to adjust it to a desired pH. be able to. The optimal amount of peptide drugs used is
Although it cannot be limited because it varies depending on the kind of drug and the disease state of the patient to be used, it is preferably contained so as to show an activity of 0.01 to 100 IU per 1 mg based on the total weight of the formulation when it is made into a solution.

The solution formulation of the present invention thus obtained can be administered using an inhaler or a nebulizer. Regarding the dose and frequency of administration, it is desirable to select an optimal administration mode in accordance with the instructions of a specialist.

[0015]

The present invention will be described in more detail with reference to examples, but the present invention is not intended to be limited to these examples.

Preparation Examples 1 to 5 : Human insulin (recombinant type: 24.0 IU / mg, Becton Dickin
son Lab Ltd. Was prepared by dissolving it in isotonic phosphate buffered saline (pH 7.0) to prepare an insulin solution. Sodium hyaluronate (hereinafter HA
-Na; molecular weight: 2.14 x 10 ⁶ , manufactured by Shiseido Co., Ltd.) were dissolved.

The concentration of human insulin in solution was determined to be 25 IU
The final concentration (% by weight) of HA was 0.05 (formulation 1) 0.075 (formulation 2) 0.1 (formulation 3) 0.175 (formulation 4) 0.25 (formulation 5). ) Was obtained.

Preparation Examples 6 to 10 : Instead of isotonic phosphate buffered saline (pH 7.0), isotonic citrate buffer (pH 4.
Preparation Examples 1-5 were repeated except that 0) was used.

The final concentration (% by weight) of HA was 0.05 (formulation 6) 0.075 (formulation 7) 0.1 (formulation 8) 0.175 (formulation 9) 0.25 (formulation 10), respectively. A formulation was obtained.

Preparation Examples 11 to 13 : Preparation Examples 6 to 13 except that the pH of the isotonic citrate buffer was changed from 4.0 to 5.0 and the final concentration (% by weight) of HA was as follows.
Repeated 10 times.

A final concentration (wt%) of HA was 0.05 (formulation 11) 0.1 (formulation 12) 0.25 (formulation 13), respectively.

Preparation Examples 14 and 15 : Preparation Examples 1 to 5 were repeated except that human calcitonin (manufactured by Beckman) was used instead of human insulin and the final concentrations of HA were set as follows.

Final HA concentrations (wt%) were 0.25 (formulation 14) and 0.5 (formulation 15), respectively.

Transpulmonary absorption experiment : Using Wistar male rats (body weight 210 to 300 g), each preparation (5 IU / 0.2 ml /) was administered from the respiratory tract according to the method of Shanker et al.
(kg body weight). Immediately before and after the administration, blood was collected from the femoral vein with time, and the plasma glucose concentration was measured. The absorbability of human insulin from the lungs was evaluated using the decrease in plasma glucose concentration, which is a pharmacological effect of insulin, as an index. The plasma glucose concentration was measured by the glucose oxidase method using a commercially available assay kit (Glucose B-Test Wako: Wako Pure Chemical Industries, Ltd.).

(1) The measurement results of the formulations 1 to 5 and the control (pH 7 buffer only, 0.1% by weight HA buffer solution) and comparison (pH 7.0 HA-free buffered insulin solution) are shown. As shown in FIG.

(2) Formulations 6 to 10 and control (pH
4.0 buffer alone, 0.1 wt% HA buffer solution) and comparison (HA-free buffered insulin solution at pH 4.0)
FIG. 2 shows the measurement results of the above.

(3) Calcium concentrations of the preparations 14 and 15 and the control (0.25% HA solution) were measured using a commercially available calcitonin assay kit (calcium C-test Wako: Wako Pure Chemical Industries, Ltd.). The measurement result is shown in FIG.

The measurement results show the average value of three or four trials, and the vertical line at each measurement point shows the deviation due to the student T test.

From the above results, it can be seen that the absorption of the drug in the body can be significantly enhanced when the HA concentration is 0.1% by weight, particularly in the insulin preparation.

[0030]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a dosage form capable of significantly enhancing the in vivo absorption of peptide drugs, particularly insulin, and also to stabilize the drug in the preparation.

[Brief description of drawings]

FIG. 1 is a graph showing the glucose level in plasma that reflects the in vivo absorption level of a drug (insulin) when the transpulmonary administration preparation according to the present invention is used.

FIG. 2 is a diagram of the case of the preparation (solution pH is 4.0)
3 is a graph showing a glucose level similar to that of FIG.

FIG. 3: Formulation according to the invention (containing calcitonin)
3 is a graph showing the in vivo absorption level of

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display area A61K 38/23 A61K 47/36 E 47/36 37/26 37/30

Claims (4)

[Claims] 1. A preparation for pulmonary administration, which comprises a combination of a peptide drug and hyaluronic acid. 2. The preparation for transpulmonary administration according to claim 1, wherein the peptide drug is insulin or calcitonin. 3. Hyaluronic acid is about 0.075 to 0.125.
The preparation for transpulmonary administration according to claim 1 or 2, which is used as an aqueous solution of wt%. 4. The preparation for transpulmonary administration according to claim 3, wherein hyaluronic acid is used as an aqueous solution of about 0.1% by weight, and the drug is insulin.