ORAL PHARMACEUTICAL COMPOSITION INCLUDING TERIPARATIDE AND METHOD FOR PREPARING SAME

Abstract

Proposed is a pharmaceutical composition for oral administration, the composition including an ionic bond complex composed of teriparatide, deoxycholic acid, Nα-deoxycholyl-L-lysyl-methylester (DCK), and di-alpha-tocopherol polyethylene glycol 1000 succinate, and a method for preparing the same is also proposed. The oral pharmaceutical composition is useful for the treatment of osteoporosis because the pharmaceutical composition can increase intestinal membrane permeability and oral administration bioavailability of teriparatide and improve patient compliance.

Claims

1. An oral pharmaceutical composition comprising an ionic bond complex composed of teriparatide, deoxycholic acid, Nα-deoxycholyl-L-lysyl-methylester, and di-alpha-tocopherol polyethylene glycol 1000 succinate.

2. The composition of claim 1, wherein the Nα-deoxycholyl-L-lysyl-methylester is contained in 0.1 to 10 moles based on 1 mole of teriparatide.

3. The composition of claim 1, wherein the deoxycholic acid is contained in 1 to 20 moles based on 1 mole of teriparatide.

4. The composition of claim 1, further comprising a poloxamer.

5. A method for preparing an oral pharmaceutical composition, the method comprising: a first step of forming an ionic complex by adding an aqueous solution of deoxycholic acid and Nα-deoxycholyl-L-lysyl-methylester to a solution including teriparatide and di-alpha-tocopherol polyethylene glycol 1000 succinate; a second step of preparing granules by mixing a binder, a disintegrant, a diluent, and a lubricant with the ionic bond complex prepared in the first step; and a third step of compressing the granules prepared in the second step in the form of tablets.

6. The method of claim 5, further comprising a step of coating the tablet prepared in the third step with an enteric material.

7. The method of claim 6, wherein the enteric material is at least one selected from the group composed of methacrylic acid-ethyl acrylate copolymer (Eudragit), hydroxypropyl methylcellulose phthalate, acetyl succinate hydroxypropyl methylcellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose, and shellac.

8. A method for preparing an oral pharmaceutical composition, the method comprising: a first step of forming an ionic complex by adding an aqueous solution of deoxycholic acid and Nα-deoxycholyl-L-lysyl-methylester to a solution including teriparatide and di-alpha-tocopherol polyethylene glycol 1000 succinate; a second step of preparing a mixture by adding caprylocaproyl mqacrogol-8 glycerides as a primary surfactant and Tween 80 as a primary auxiliary surfactant to the ionic bond complex solution; a third step of preparing a water-in-oil (w/o) primary nano-emulsion by dispersing the mixture of the second step on a primary oil phase; and a fourth step of preparing a water-in-oil-in-water (w/o/w) secondary nano-emulsion by adding a mixture of Cremopore or Twin 80 as a secondary surfactant and polyethylene glycol 400 as a secondary auxiliary surfactant to the water-in-oil (w/o) primary nano-emulsion of the third step.

9. The method of claim 8, wherein the primary oil phase is at least one selected from the group composed of silicone oil, ester-based oil, hydrocarbon-based oil, propylene glycol monocaprylate, propylene glycol dicaprylocaprate, oleoyl macrogol-6 glycerides, lauroyl macrogol-6 glycerides, linoleic oil macrogol-6 glycerides, medium-chain triglycerides, oleic acid, stearic acid, glyceryl behenate, glycerol monostearate, and castor oil.

10. The method of claim 8, wherein the primary oil phase in the w/o/w secondary nano-emulsion is contained in an amount of 0.1 to 40% by weight based on the total weight of the composition.

11. The method of claim 8, wherein the mixture of the primary surfactant and the primary auxiliary surfactant and the mixture of the secondary surfactant and the secondary auxiliary surfactant are contained in an amount of 0.1 to 40% by weight based on the total weight of the composition.

12. The method of claim 8, wherein the primary and secondary auxiliary surfactants are mixed with the primary and secondary surfactants, respectively, each independently in a weight ratio of 1:0.1 to 1:10.

13. The method of claim 8, wherein the di-alpha-tocopherol polyethylene glycol 1000 succinate is contained in an amount of 0.1 to 100 parts per 1 part by weight of teriparatide.

Description

DESCRIPTION OF DRAWINGS

[0050] FIG. 1 shows the results of confirming the bioavailability of teriparatide according to Examples 1 and 4 of the present disclosure.

BEST MODE FOR DISCLOSURE

[0051] Hereinafter, the present disclosure will be described in more detail through examples. These examples are only for showing the present disclosure, and therefore, the scope of the present disclosure is not to be construed as being limited by these examples.

[0052] Preparation Example: Preparation of Deoxycholic Acid Derivatives

[0053] Deoxycholic acid derivatives were prepared by chemically binding positively charged lysine to deoxycholic acid. First, 26 g of deoxycholic acid is dissolved in 800 mL of tetrahydrofuran. Separately 20 g of HLys(Boc)-OMe.HCl is dissolved in a mixed solvent of 7.4 mL of N-methyl morpholine and 6.4 mL of ethyl chloroformate. An HLys(Boc)-OMe.HCl solution was added to the deoxycholic acid solution, followed by stirring for 30 minutes, and then refluxed for 2 hours. The reaction precipitate obtained by stirring at room temperature overnight was filtered, and then the residual solvent was evaporated. The dried precipitate is purified through column chromatography using chloroform and methanol and then dissolved in a mixed solvent of acetyl chloride and methanol in a cooling water bath (ich batch). After removing the solvent, the residue was dissolved in water again, washed three times with chloroform, and then a water layer was taken and freeze-dried to prepare Nα-deoxycholyl-L-lysyl-methylester (DCK), which is a deoxycholic acid derivative.

Example 1 and Comparative Example: Preparation of Ionic Bond Complexes of Teriparatide, Deoxycholic Acid, Deoxycholic Acid Derivatives, and Solubilizing Agent

[0054] After dissolving teriparatide and di-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) as a solubilizer in purified water, an aqueous solution of a deoxycholic acid derivative prepared separately is slowly added while stirring to prepare an ionic bond complex. At this time, the deoxycholic acid derivative aqueous solution is slowly added so that the molar ratio of teriparatide and the deoxycholic acid derivative, Nα-deoxycholyl-L-lysyl-methylester (DCK) is 1:2 or 1:4. Then, an ionic bond complex is prepared by slowly adding an aqueous sodium deoxycholic acid solution prepared separately while stirring the complex solution. At this time, an aqueous solution of deoxycholic acid is slowly added so that the molar ratio of teriparatide and deoxycholic acid is 1:4 or 1:8. The final mixture was centrifuged and then freeze-dried to prepare powdery teriparatide and deoxycholic acid derivatives, teriparatide and deoxycholic acid, or teriparatide, and a mixture composite thereof by the composition of Table 1 below.

[0055] In addition, as a Comparative Example, the complex was prepared without deoxycholic acid using poloxamer, caprylocaproyl macrogol-8 glycerides (trade name: Labrasol), and Cremophor as a solubilizing agent.

TABLE-US-00001 TABLE 1 Comparative Comparative Comparative Comparative Comparative Comparative Comparative Ingredient Example example example example example example example example name 1 1 2 3 4 5 6 7 Teriparatide 0.1  0.1 0.1  0.1 0.1 0.1  0.1  0.1  Deoxycholic  0.056 — 0.056 0.056 0.056 0.056 0.056 0.056 acid derivative Deoxycholic 0.08 — — — — — — — acid TPGS 7.52 — — — 7.52 — — 7.52  Poloxamer — — — 10 10 — — — Labrasol — — — — — 7.52  — — Cremophor — — — — — — 7.52  — Total 7.76 0.1 1.056 10.056 17.676 7.676 7.676 7.676 weight (mg)

Experimental Example 1: Confirmation of the Artificial Intestinal Membrane Permeability of the Complex Composed of Teriparatide, Deoxycholic Acid, Deoxycholic Acid Derivatives, and Solubilizing Agents

[0056] Effective permeability (Pe) through the artificial intestinal membrane of Examples 1 and Comparative Examples 1 to 7 prepared above was evaluated using the parallel artificial membrane permeability assay (PAMPA), which is an artificial intestinal membrane permeability evaluation system. First, the samples of Example 1 and Comparative Examples 1 to 7 were dissolved in phosphate buffer (PBS, pH 6.8) to a concentration of 200 μg/mL as teriparatide, and then 200 μL each was added to the donor part of the PAMPA system, and 300 μL of phosphate buffer (PBS, pH 6.8) was filled in the receiving part of the PAMPA system. Thereafter, the donor part and the receiving part were combined and left at room temperature for 5 hours. Then, the solution of each well of the receiving part and the donor part was filtered through a membrane filter having a pore diameter of 0.45 μm, and then the concentration of teriparatide permeated through the artificial intestinal membrane was analyzed using the HPLC system under the following conditions.

[0057] 50 μL of each sample was injected into the HPLC system, and acetonitrile (B) containing 0.1% (w/v) trifluoroacetic acid (TFA) aqueous solution (A) and 0.1% (w/v) TFA as mobile phases were separated by linearly changing the composition of mobile phase B from 51% to 76% for 25 minutes at a flow rate of 1.0 mL/min. Teriparatide was measured at 220 nm, and the effective transmittance (Pe) through the artificial intestinal membrane was calculated by Formula 1 below.

P.sub.e=−ln[1−C.sub.R(t)/C.sub.equilibrium]/[S×(1/V.sub.D+1/V.sub.R)×t]  [Formula 1]

[0058] Where Pe is the effective transmittance (cm/s), S is the effective permeation area (0.288 cm.sup.2), VD is the solution volume of the donor part well (0.2 mL), VR is the solution volume of the receiving part well (0.3 mL), t is the sampling time (s), CR(t) is the drug concentration in the receiving part at time t, C.sub.equilibrium is [CD (t)×VD CR (t)×VR]/(VD+VR), and CD(t) is the drug concentration at the donor part.

[0059] The results of calculating the effective transmittance through the artificial intestinal membrane of Example 1 and Comparative Examples 1 to 7 using the above Formula are shown in Table 2 below.

TABLE-US-00002 TABLE 2 Effective transmittance (P.sub.e, ×10.sup.−6 cm/s) Example 1 14.9 ± 4.79 Comparative 0.582 ± 0.132 example 1 Comparative  2.36 ± 0.646 example 2 Comparative 7.57 ± 2.09 example 3 Comparative 11.9 ± 3.38 example 4 Comparative 8.27 ± 2.47 example 5 Comparative 6.52 ± 1.27 example 6 Comparative 9.07 ± 3.39 example 7 *Each value means mean ± standard deviation (n = 4).

[0060] As a result, as can be seen in Table 2 above, in the case of Comparative Example 2, in which a complex of the deoxycholic acid derivative to teriparatide was formed in a ratio of 1:4 mol, compared to Comparative Example 1, teriparatide permeability through the artificial intestinal membrane increased by 4.05 times. This is considered to be due to the fact that the deoxycholic acid derivative itself increased the lipid solubility of the teriparatide and improved lipid permeability to the intestinal membrane.

[0061] However, when a solubilizing agent such as TPGS, poloxamer, caprylocaproyl mqacrogol-8 glycerides (Labrasol), and Cremophor is added during complex formation of teriparatide and a deoxycholic acid derivative, teriparatide permeability increases 3.84 times, 3.21 times, 3.50 times, and 2.76 times, respectively, compared to the permeability of the 1:4 molar ratio complex of the teriparatide and the deoxycholic acid derivative. In particular, in the case of a complex using TPGS as a solubilizing agent as in Example 1, the artificial intestinal membrane permeability increased by 25.6 times and 6.31 times, respectively, compared to teriparatide (Comparative Example 1) and a 1:4 molar ratio complex of teriparatide and deoxycholic acid derivatives (Comparative Example 2).

[0062] In addition, in the case of the complex using TPGS as a solubilizing agent as in Example 1, the artificial intestinal membrane permeability was increased compared to Comparative Examples 3, 5, and 6 using poloxamer, Labrasol, and Cremophor as the solubilizing agent.

[0063] Moreover, the artificial intestinal membrane permeability of Example 1 of the present disclosure using TPGS alone was increased compared to Comparative Example 4 in which TPGS and poloxamer were used together as a solubilizing agent.

[0064] In addition, the artificial intestinal membrane permeability of Example 1 of the present disclosure containing both deoxycholic acid and deoxycholic acid derivatives was increased compared to Comparative Example 7 containing deoxycholic acid derivatives Nα-deoxycholyl-L-lysyl-methylester (DCK) and TPGS without deoxycholic acid.

[0065] These results are considered to be due to the lipid affinity enhancing effect of the deoxycholic acid derivative itself and the solubilizing action of the intestinal lipid membrane by the solubilizing agent, in particular, the lipid affinity enhancing effect of teriparatide according to the intestinal lipid membrane solubilizing action appears to be due to the combination of deoxycholic acid and deoxycholic acid derivatives and TPGS.

Experimental Example 2: Confirmation of Permeability Through Intestinal Cell Membrane of the Complex Composed of Teriparatide, Deoxycholic Acid, Deoxycholic Acid Derivatives, and Solubilizing Agent

[0066] The apparent permeability of the complexes prepared as in Example 1 and Comparative Examples 1 to 7 to the intestinal cell membrane, Caco-2 cell membrane, was evaluated as follows. After Caco-2 cells were treated at a concentration of 1×105 cells/mL in 24-well Transwell, respectively, and after culturing the cells for 14 to 16 days, a cell monolayer of the electrical resistance (TEER) value through the Caco-2 cell membrane was >350 Ω.Math.cm.sup.2 was used for the experiment. First, the medium was removed from the Transwell, and then the donor part and receiving part were filled with HBSS and cultured at 37° C. for 20 minutes, then the TEER value was measured again, and then HBSS was removed. Thereafter, 0.1 mL of the drug solution in which the samples of Examples 1 and Comparative Examples 1 to 7 were dissolved at 200 μM as teriparatide in HBSS was applied to the donor part of each Transwell, and the receiving part was filled with 0.6 mL of HBSS and cultured at 37° C. At 0.5, 1, 2, 3, 4, and 5 hours, 100 μL samples were collected from the receiving part, filtered using a membrane filter (pore 0.45 μm, PVDF), and the concentration of teriparatide permeated through the intestinal cell membrane was analyzed by HPLC under the conditions mentioned in Experimental Example 1. Apparent intestinal cell membrane permeability (Papp) was calculated using Formula 2 below, and the results are shown in Table 3.

P.sub.app=dQ/dt×1/(S×C.sub.i)  [Formula 2]

[0067] Where dQ/dt means the permeation rate (μmol/h) of the drug to the donor part, and S means the permeation area (cm.sup.2). C.sub.i means the initial concentration (μM) of the drug at the donor part.

TABLE-US-00003 TABLE 3 Apparent transmittance (P.sub.app, ×10.sup.−6 cm/s) Example 1 4.70 ± 0.589 Comparative 0.362 ± 0.045  example 1 Comparative 1.04 ± 0.241 example 2 Comparative 2.01 ± 0.517 example 3 Comparative 3.56 ± 0.610 example 4 Comparative 1.90 ± 0.486 example 5 Comparative 1.68 ± 0.408 example 6 Comparative 3.13 ± 0.467 example 7 * Each value means mean ± standard deviation (n = 4).

[0068] As a result, as shown in Table 3 above, the permeability through the intestinal cell membrane of the complex formed of teriparatide and deoxycholic acid derivative in a molar ratio of 1:4 (Comparative Example 2) was increased by 2.87 times compared to the teriparatide (Comparative Example 1). This effect of increasing intestinal membrane permeability of drugs by deoxycholic acid derivatives is due to the improvement of lipophilicity of drugs as well as the enhancement of cell membrane permeability of drugs resulting from selective and specific binding of deoxycholic acid to bile acid carriers present on the surface of the intestinal cell membrane.

[0069] However, in the deoxycholic acid derivative molecule bonded to a molecule of hydrophilic teriparatide peptide, the complex molecule itself foams a self-assembled micelle due to hydrophobicity so that the deoxycholic acid derivative molecule is located in the inner core of the micelle, which degrades specific interaction with the bile acid carrier present in the intestinal cell membrane. Therefore, in order to inhibit the formation of self-assembled micelles of such complexes, when solubilizing agents such as TPGS, poloxamer, caprylocaproyl mqacrogol-8 glycerides (Labrasol), and Cremopores are added in the ionic bond complex preparation process of the teriparatide-deoxycholic acid derivatives as in Example 1 and Comparative Examples 3 to 7, the intestinal cell membrane permeability was increased by 3.01 times, 1.93 times, 1.83 times, and 1.62 times, respectively, compared to the complex of teriparatide-deoxycholic acid derivative (Comparative Example 2) due to the increase in specific interactions of the deoxycholic acid derivative with the bile acid carriers and the synergistic effect of improving the solubility of the solubilizer itself. In particular, in the case of a complex using TPGS as a solubilizing agent as in Example 1, the artificial intestinal membrane permeability was increased by 13.0 times and 4.52 times, respectively, compared to teriparatide (Comparative Example 1) and a 1:4 molar ratio complex of teriparatide and deoxycholic acid derivatives (Comparative Example 2).

[0070] In addition, in the case of the complex using TPGS as a solubilizing agent as in Example 1, the intestinal cell membrane permeability was increased compared to Comparative Examples 3, 5, and 6 using poloxamer, Labrasol, and Cremophor as the solubilizing agent.

[0071] Moreover, the intestinal cell membrane permeability of Example 1 of the present disclosure using TPGS alone was increased compared to Comparative Example 4 in which TPGS and poloxamer were used together as a solubilizing agent.

[0072] In addition, the artificial intestinal membrane permeability of Example 1 of the present disclosure containing both deoxycholic acid and deoxycholic acid derivatives was increased compared to Comparative Example 7 containing deoxycholic acid derivatives Nα-deoxycholyl-L-lysyl-methylester (DCK) and TPGS without deoxycholic acid.

[0073] These results are considered to be due to the lipid affinity enhancing effect of the deoxycholic acid derivative itself and the solubilizing action of the intestinal lipid membrane by the solubilizing agent, in particular, the lipid affinity enhancing effect of teriparatide according to the intestinal lipid membrane solubilizing action appears to be due to the combination of deoxycholic acid and deoxycholic acid derivatives and TPGS.

Example 2: Preparation of an oral solid preparation including a complex composed of teriparatide, deoxycholic acid, a deoxycholic acid derivative, and a solubilizing agent

[0074] The complex composed of teriparatide, deoxycholic acid, deoxycholic acid derivative, and TPGS prepared in Example 1 was mixed with other additives shown in Table 4 below and subjected to a wet granulation process. The prepared granules were dried, mixed with magnesium stearate, and compressed into an appropriate form to prepare tablets or filled in hard capsules. The composition of the obtained matrix tablet and capsule contents are shown in Table 4 below.

TABLE-US-00004 TABLE 4 Ingredient (mg) Example 2 Teriparatide 0.1 Deoxycholic acid derivatives 0.056 Deoxycholic acid 0.08 TPGS 7.52 Polyvinylpyrrolidone 12.48 Cross-linked sodium 10 carboxymethylcellulose Microcrystalline Cellulose 34.382 Lactose 34.382 Magnesium stearate 1 Moisture* Appropriate amount Total amount 100 *Removed during manufacturing.

Example 3: Coating of matrix tablets containing teriparatide complex

[0075] The matrix tablet prepared in Example 2 was primarily coated with hydroxypropyl methyl cellulose 2910 and then secondarily coated with hydroxypropyl methyl cellulose phthalate, which is an enteric coating agent containing a pigment, to prepare the tablet of Example 3. At this time, the composition of the coating solution is shown in Table 5 below, and the coating was spray-coated with a pan coater.

TABLE-US-00005 TABLE 5 Division Ingredient Example 3 Primary Hydroxypropyl methyl  5* coating cellulose 2910 Primary Triethyl citrate   0.5* coating Secondary Hydroxypropyl methyl 12* enteric cellulose phthalate coating *The ratio of the coating to the uncoated core matrix tablet is expressed in % by weight.

Example 4: Preparation of Oral Water-In-Oil-In-Water Type (w/o/w) Nano-Emulsion Containing Complex Composed of Teriparatide, Deoxycholic Acid, Deoxycholic Acid Derivative, and Solubilizing Agent

[0076] After redispersing 17.76 mg of the complex of the teriparatide, deoxycholic acid, the deoxycholic acid derivative, and the TPGS (corresponding to 0.1 mg of teriparatide) prepared in Example 1 in 38 mg of purified water, 112 mg of 1:1 mixture of a primary surfactant and a primary auxiliary surfactant (Labrasol:Tween 80=1:1, w/w) was added and mixed, and then 50 mg of Labrafil M1944 in an oil phase was added and mixed to prepare a w/o nano-emulsion. A liquid oral nano-emulsion was prepared by adding 630 mg of a mixture of secondary surfactant and secondary auxiliary surfactant (Tween 80:Cremophor EL:PEG400=1:2:2, w/w/w).

Experimental Example 3: Confirmation of Rat Bioavailability of Oral Formulations

[0077] After anesthesia by intraperitoneal injection of ketamine (45 mg/kg) and xylazine (5 mg/kg) to female Sprague-Dawley rats (200-250 g, 6-7 weeks old), the abdomen of the rat was cut to take out the small intestine, and Examples 1 and 4 and Comparative Examples 1 and 2 prepared above were dispersed in purified water, and then injected into a proximal jejunum in an amount corresponding to 100 μg/kg as teriparatide by 400 μL. In addition, in order to evaluate the relative bioavailability, 150 μL of teriparatide solution dissolved in physiological saline was subcutaneously injected at an amount corresponding to 20 μg/kg as teriparatide.

[0078] After drug administration, blood samples were collected 150 μL at regular time intervals and mixed with 3.8% aqueous sodium citrate solution of 50 μL. Thereafter, the blood sample was centrifuged for 15 minutes at 2,500×g, at 4° C., and plasma was collected and stored at −70° C. The teriparatide concentration in plasma was measured at a wavelength of 620 nm using the human PTH (1-34) ELISA kit (ALPCO Diagnostics, USA). The pharmacokinetic parameters are estimated through the non-compartment method using WinNonlin S Software (ver. 5.3; Pharsight Corporation, USA) and are shown in Table 6 and FIG. 1.

TABLE-US-00006 TABLE 6 Substance to be Comparative Comparative administered Teriparatide example 1 example 2 Example 1 Example 4 Route of Subcutaneous Dosing in Dosing in Dosing in Dosing in administration injection jejunum jejunum jejunum jejunum Dosage as 0.02 0.1 0.1 0.1 0.1 teriparatide (mg/kg) T.sub.max.sup.a (h) 0.25 ± 0.00 0.33 ± 0.14 0.42 ± 0.14 0.50 ± 0.25 0.58 ± 0.14 C.sub.max.sup.b 0.805 ± 0.209 0.041 ± 0.010 0.449 ± 0.108 0.583 ± 0.106 0.710 ± 0.165 (ng/mL) AUC.sub.last.sup.c 0.734 ± 0.191 0.030 ± 0.007 0.528 ± 0.128 0.732 ± 0.133 0.893 ± 0.208 (ng .Math.) sh/mL) AUC.sub.inf.sup.d 0.765 ± 0.199 0.031 ± 0.007 0.556 ± 0.134 0.736 ± 0.134 0.897 ± 0.209 (ng .Math.) sh/mL) Bioavailability.sup.e 100 0.810 ± 0.191 14.4 ± 3.48 20.0 ± 3.63 24.3 ± 5.66 (%) .sup.aT.sub.max, time to reach Cmax .sup.bC.sub.max, maximum plasma concentration .sup.cAUC.sub.last, the area under the plasma concentration-time curve from 0 to the last plasma concentration measurement time .sup.dAUC.sub.inf, plasma concentration from 0 to infinity − area under the time curve .sup.eBioavailability, (AUC.sub.last, jejunum/dose teriparatide, jejunum)/(AUC.sub.last, subcutaneous injection/dose teriparatide, subcutaneous injection) × 100 Each value means mean ± standard deviation (n = 4).

[0079] FIG. 1 shows the concentration of teriparatide in plasma over time after administration of a drug to a rat. After administration of 0.1 mg/kg teriparatide of Comparative Example 1 intrajejunal, the maximum drug concentration (C.sub.max) in plasma was 0.041±0.010 ng/mL, the area under the time-concentration curve (AUC.sub.last) was 0.030±0.007 ng.Math.h/mL, and the relative bioavailability compared to subcutaneous injection was evaluated to be 0.810±0.191%. On the other hand, when comparing the case where 0.1 mg/kg as teriparatide of the 1:4 molar complex of the teriparatide-deoxycholic acid derivative (Comparative Example 2) was administered in the jejunum and the case where 0.1 mg/kg of teriparatide alone was administered in the jejunum, in case of a complex of the teriparatide-deoxycholic acid derivative, C.sub.max was 11 times, AUC.sub.last was 17.6 times, and relative bioavailability compared to subcutaneous injection was increased by 17.8 times. On the other hand, when the complex of teriparatide, deoxycholic acid, a deoxycholic acid derivative, and TPGS of Example 1 was administered, compared to which Comparative Example 1 (teriparatide alone) or Comparative Example 2 (teriparatide and deoxycholic acid derivative 1:4 molar complex) was administered, respectively, C.sub.max was increased by 14.2 times and 1.30 times, AUC.sub.last was increased by 24.4 times and 1.39 times, respectively, and relative bioavailability compared to subcutaneous injection increased by 24.7 times and 1.39 times, respectively. In the case of the oral nano-emulsion of Example 4, including a complex of teriparatide, deoxycholic acid, a deoxycholic acid derivative, and TPGS of Example 1, C.sub.max and AUC.sub.last were increased by 17.3 times and 29.8 times, respectively, compared to Comparative Example 1 (teriparatide alone) and the relative bioavailability compared to subcutaneous injection was evaluated as 24.3±5.66%, increasing by 30 times.