Patent Description:
The technology of making drugs orally available has always been a research hotspot. This technology relates to realizing oral administration of enteric capsules of a drug substance that is conventionally administered via subcutaneous or intravenous injection only, such that the drug is delivered to the small intestine where it disintegrates, and is absorbed through the small intestine into the blood circulation with the assistance of a combination of different formulants.

In comparison with drugs for subcutaneous or intravenous administration, drugs for oral administration have two advantages: for patients, the drugs can be self-administered, are more acceptable, and pose a lower risk of infection; and for drug manufacturers, the drugs set out more lenient requirements on workshop conditions and allow reduced production costs.

However, there are also many obstacles and bottlenecks encountered in this field, such as how to prevent drugs from being degraded by various digestive enzymes in the intestinal microenvironment, how to promote smooth passage of drugs through small-intestinal villous epithelial cells, and how to minimize the side effects of orally administered formulations.

Orally administered drugs enter the blood circulation mainly through the carrier transport, pinocytosis, or the paracellular pathway. The influencing factors include the relative molecular mass, spatial structure and hydrophobicity of the drugs, as well as various barriers in the body, such as the acid barrier, enzymatic barrier and membrane barrier. In addition, the first pass effect after the drugs enter the portal venous system through the gastrointestinal tract and enter the liver is also a problem that must be addressed to make drugs available for oral administration.

So far, in studies for orally available polypeptide drugs, the strategies to improve absorption of orally administered drugs mainly include chemical modification, addition of absorption enhancers, addition of enzyme inhibitors, nanocarriers, liposome carriers, and micro-emulsion carriers. <CIT> discloses oral pharmaceutical compositions for the enteric delivery of polypeptides.

For the above reasons, the applicant conducted extensive creative studies and discovered a novel composition prepared from a surfactant, an acrylic polymer, chitin or its derivatives, and a metal ion chelating agent. Studies have demonstrated that the composition according to the present invention can be prepared into a composite adjuvant which can, after combined with pharmaceutically active ingredients, improve absorption of the active ingredients in the small intestine. The composition according to the present invention is an organic whole that synergistically ensures absorption of a drug (effective ingredients or active ingredients) in the intestine.

The present invention is achieved through a pharmaceutical composition for oral formulation, comprising a drug and an adjuvant, wherein the drug is polypeptide, insulin, or growth hormone; the adjuvant is composed of: a surfactant, an acrylic polymer, chitin or its derivatives, and a metal ion chelating agent; the surfactant is sodium lauryl sulfate, the acrylic polymer is carbomer, the chitin or its derivatives are chitosan, and the metal ion chelating agent is sodium citrate. Below, claimed variants of the pharmaceutical composition are listed.

Provided is a pharmaceutical composition, comprising: a surfactant, an acrylic polymer, chitin or its derivatives, and a metal ion chelating agent according to claim <NUM>. surfactant is sodium lauryl sulfate, the acrylic polymer is carbomer, the chitin or its derivatives are chitosan, and the metal ion chelating agent is sodium citrate.

The composition may be used to ensure absorption of drugs (effective ingredients or active ingredients) in the small intestine.

The composition may be used to promote absorption of drugs (effective ingredients or active ingredients) in the small intestine.

The surfactant, the acrylic polymer, the chitin or its derivatives, and the metal ion chelating agent may be in a weight ratio of <NUM>-<NUM>:<NUM>-<NUM>:<NUM>-<NUM>:<NUM>-<NUM>.

Preferably, the surfactant, the acrylic polymer, the chitin or its derivatives, and the metal ion chelating agent may be in a weight ratio of <NUM>-<NUM>:<NUM>-<NUM>:<NUM>-<NUM>:<NUM>-<NUM>.

The drugs (effective ingredients or active ingredients) include polypeptides. The polypeptides include Exenatide, Nesiritide, Gonadorelin, Leuprolide, recombinant Glucagon, Oxytocin, Bivalirudin, Sermorelin, Gramicidin D, recombinant Insulin, Vasopressin, Cosyntropin, Octreotide, Vapreotide, Mecasermin, Teriparatide, ACTH, Pramlintide, Abaloparatide, rhGH, thymosin alpha-<NUM>, and the like.

The drugs (effective ingredients or active ingredients) include insulin.

The drugs (effective ingredients or active ingredients) include growth hormon.

Also provided is a composition promoting intestinal absorption, which is prepared from raw materials comprising a surfactant, an acrylic polymer, chitin or its derivatives, and a metal ion chelating agent.

The composition promoting intestinal absorption described above may be prepared into an adjuvant for use in an oral formulation.

The composition according to the present invention may be prepared as a novel adjuvant that enables oral administration of drugs (effective ingredients or active ingredients) which were previously for injection only and not for oral administration, thereby changing the administration route of the drugs (effective ingredients or active ingredients).

The composition according to the present invention can ensure intestinal absorption of drugs (effective ingredients or active ingredients) that are easily decomposed in the gastrointestinal tract.

The composition according to the present invention can promote intestinal absorption of drugs (effective ingredients or active ingredients) that are not easily absorbed in the gastrointestinal tract.

Since the composition according to the present invention promotes small-intestinal absorption which requires release of drugs in the small intestine to perform its functions, in pharmacodynamic and pharmacokinetic tests, drugs were administered to rodents by a small-intestinal catheter, or to mammals orally in the form of enteric capsules.

In the present invention, the composition was combined with each of the aforementioned polypeptides and tested for bioavailability in rodents, and meanwhile some polypeptides were selected for pharmacodynamic and pharmacokinetic tests on different animals.

The following specific examples are given to illustrate technical solutions of the present invention.

The examples shown in this specification only exemplify the embodiments of the inventive concept.

The following experiments according to the present invention are conclusive experiments conducted by the inventors based on many creative experiments, representing the technical solutions of the present invention to be claimed. The quantitative tests in the following Examples are all from triplicate experiments, and the data is given as the average or the average ± standard deviation of the triplicate experiments.

The composition: sodium lauryl sulfate as the surfactant, carbomer as the acrylic polymer, chitosan as the chitin or its derivatives, and sodium citrate as the metal ion chelating agent, in a weight ratio of <NUM>:<NUM>:<NUM>:<NUM>.

Exenatide and the above composition were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

Laboratory animals: SD male rats, intraperitoneally injected with <NUM>/kg STZ to establish a hyperglycemia model.

Small intestine efficacy test: administration was through subcutaneous injection (sc) or a small-intestine catheter (ei), and blood samples were collected at <NUM>, <NUM>, <NUM> and <NUM> to measure the blood sugar.

The results show that, in the absence of the composition described above, Exenatide after small-intestine administration showed a very weak hypoglycemic effect. When its dose reached <NUM>/kg, the hypoglycemic efficiency after <NUM> was merely about <NUM>%, far lower than the hypoglycemic efficiency of about <NUM>% achieved by its subcutaneous dose of <NUM>µg/kg. However, after addition of the composition of the present invention, a dose of <NUM>µg/kg can achieve the hypoglycemic effect achieved by a subcutaneous dose of <NUM>µg/kg.

Exenatide and the composition of Example <NUM> were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Exenatide was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Exenatide was <NUM>µg/kg. In another group, Exenatide at <NUM>µg/kg together with the composition of Example <NUM> of the present invention was administered via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

In order to avoid hypoglycemia in the animals, <NUM>/kg glucose was given before administration.

ELISA assay: Coating with a mouse monoclonal antibody against the target polypeptide, blocking with <NUM>% BSA, incubating with a blood sample or a standard diluted with <NUM>% BSA, capturing with Biotin-labeled rabbit polyclonal antibody against the target polypeptide, incubating with HRP-conjugated strepavidin, then developing with TMB, which was stopped with HCl, and reading at <NUM>. A standard curve was obtained from standards, and the concentration of the target polypeptide in the plasma was calculated.

AUC was calculated based on the PK curve, and the bioavailability of small-intestinal administration was calculated with respect to <NUM>% of the bioavailability of intravenous injection (iv).

The results showed that the AUC in the PK curve for <NUM>µg/kg i. injected Exenatide was <NUM> ng/ml. h, while the blood concentration after the small-intestinal injection of <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of Example <NUM>, the AUC in the PK curve could reach <NUM> ng/ml. h, and the bioavailability of small-intestinal administration was about <NUM>%. The test results are shown in <FIG> and <FIG>.

<NUM> of Exenatide was mixed thoroughly with <NUM> of the composition of Example <NUM>, freeze-dried, loaded into a #<NUM> enteric capsule, and reserved for further use;.

<NUM> of Exenatide was mixed thoroughly with <NUM> of the composition of Example <NUM>, freeze-dried, loaded into a #<NUM> normal capsule, and reserved for further use;.

<NUM> of Exenatide was mixed thoroughly with <NUM> of mannitol, freeze-dried, loaded into a #<NUM> enteric capsule, and reserved for further use.

Laboratory animals: adult male beagle dogs.

PK test for oral administration: The enteric capsules were orally administered to fasted animals, and then blood samples were collected after <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>. The blood samples were anticoagulated with <NUM> EDTA, and centrifuged at <NUM> at <NUM> rpm for <NUM>. Plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Exenatide was injected intravenously to fasted animals at <NUM>. 3µg/kg, and then blood samples were collected after <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>. The blood samples were anticoagulated with <NUM> EDTA, and centrifuged at <NUM> at <NUM> rpm for <NUM>. Plasma was collected and subjected to quick freezing. See <FIG> and <FIG>.

In order to avoid hypoglycemia in animals, <NUM>/kg glucose was given before administration.

The PK data for beagle dogs show that the AUC of <NUM>µg/kg intravenously injected Exenatide was about <NUM> ng/ml. h, and the AUC of <NUM> orally administered Exenatide/the composition of Example <NUM> was about <NUM> ng/ml. The bioavailability of orally administered Exenatide/Composition of Example <NUM> was about <NUM>%.

Without the assistance of the composition of the present invention, Exenatide cannot successfully enter the blood. After addition of the composition of the present invention, the efficiency of entering the blood was significantly improved. As the weight of the composition of Example <NUM> increased, the efficiency of Exenatide entering the blood also slightly increased, but to a limited degree. Considering convenience of oral administration and effectiveness of drugs, the dose of #<NUM> capsules was more appropriate.

<NUM> of Exenatide was mixed thoroughly with <NUM> of the composition of Example <NUM>, freeze-dried, loaded into a #<NUM> enteric capsule, and reserved for further use.

Physical examination and adaptation of animals: Blood samples from fasted animals were collected to test blood biochemical indicators. Once everything was confirmed normal, the animals were placed in a quiet room to adapt for <NUM> week. The daily feeding time and feeding amount were required to be consistent.

Data collection before modeling: Blood samples were collected at <NUM> time points every day (before feeding, and <NUM>, <NUM>, <NUM> after feeding) for <NUM> consecutive days.

Modeling: an Alloxan solution was intravenously injected at <NUM>/kg to fasted animals. One week later, blood samples were collected at <NUM> time points every day (before feeding, and <NUM>, <NUM>, <NUM> after feeding) for <NUM> consecutive days. Qualification of the model was evaluated based on the collected data. If the model was qualified, the efficacy test was started.

Efficacy test: Animals swallowed the test capsules before feeding, and blood samples were collected at <NUM> time points (before feeding, and <NUM>, <NUM>, <NUM> after feeding).

The results show that the Exenatide/the composition of Example <NUM> can significantly inhibit the increase in postprandial blood sugar of Alloxan-modelled beagle dogs.

The composition Tween <NUM>, carbomer <NUM>, carboxymethyl chitosan, and sodium tartrate, in a weight ratio of <NUM>:<NUM>:<NUM>:<NUM>.

PK test for small-intestinal administration: Nesiritide was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Nesiritide was <NUM>µg/kg. In another group, Nesiritide at <NUM>µg/kg together with the above composition was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Nesiritide was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Nesiritide after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the above composition, the bioavailability of small-intestinal administration could reach <NUM>%.

The composition sodium taurocholate, carbomer 934P, alkylated chitosan, and sodium maleate, in a weight ratio of <NUM>:<NUM>:<NUM>:<NUM>.

Gonadorelin and the above composition were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Gonadorelin was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Gonadorelin was <NUM>µg/kg. In another group, Gonadorelin at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Gonadorelin was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Gonadorelin after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM><NUM>%.

The composition polyethylene glycol <NUM>, carbomer, chitosan oligosaccharide, and citric acid, in a weight ratio of <NUM>:<NUM>:<NUM>:<NUM>.

Leuprolide and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Leuprolide was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Leuprolide was <NUM>µg/kg. In another group, Leuprolide at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Leuprolide was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Leuprolide after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM><NUM>%.

The composition of the present invention: Tween <NUM>, Carbomer <NUM>, carboxymethyl Chitosan, and Sodium Tartrate, in a weight ratio of <NUM>:<NUM>:<NUM>:<NUM>.

Teduglutide and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Teduglutide was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Teduglutide was <NUM>µg/kg. In another group, Teduglutide at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Teduglutide was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Teduglutide after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

The composition sodium lauryl sulfate, carbomer <NUM>, water-soluble chitosan, disodium edetate, in a weight ratio of <NUM>:<NUM>:<NUM>:<NUM>.

Oxytocin and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Oxytocin was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Oxytocin was <NUM>µg/kg. In another group, Oxytocin at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Oxytocin was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Oxytocin after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

The composition sodium lauryl sulfate, carbomer, chitosan, and citric acid, in a weight ratio of <NUM>:<NUM>:<NUM>:<NUM>.

Bivalirudin and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Bivalirudin was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Bivalirudin was <NUM>µg/kg. In another group, Bivalirudin at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Bivalirudin was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Bivalirudin after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

The composition of the present invention: sodium lauryl sulfate, carbomer, chitosan, and sodium citrate, in a weight ratio of <NUM>:<NUM>:<NUM>:<NUM>.

Sermorelin and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Sermorelin was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Sermorelin was <NUM>µg/kg. In another group, Sermorelin at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Sermorelin was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Sermorelin after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

Gramicidin and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Gramicidin was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Gramicidin was <NUM>µg/kg. In another group, Gramicidin at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Gramicidin was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Gramicidin after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

rInsulin and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: rInsulin was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of rInsulin was <NUM>µg/kg. In another group, rInsulin at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: rInsulin was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of rInsulin after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

Vasopressin and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Vasopressin was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Vasopressin was <NUM>µg/kg. In another group, Vasopressin at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Vasopressin was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Vasopressin after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

Cosyntropin and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Cosyntropin was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Cosyntropin was <NUM>µg/kg. In another group, Cosyntropin at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Cosyntropin was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Cosyntropin after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

Octreotide and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Octreotide was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Octreotide was <NUM>µg/kg. In another group, Octreotide at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Octreotide was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Octreotide after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

Mecasermin and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Mecasermin was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Mecasermin was <NUM>µg/kg. In another group, Mecasermin at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Mecasermin was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Mecasermin after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

Teriparatide and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Teriparatide was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Teriparatide was <NUM>µg/kg. In another group, Teriparatide at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Teriparatide was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Teriparatide after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

ACTH and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: ACTH was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of ACTH was <NUM>µg/kg. In another group, ACTH at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: ACTH was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of ACTH after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

Pramlintide and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Pramlintide was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Pramlintide was <NUM>µg/kg. In another group, Pramlintide at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Pramlintide was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Pramlintide after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

Vapreotide and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Vapreotide was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Vapreotide was <NUM>µg/kg. In another group, Vapreotide at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Vapreotide was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Vapreotide after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

Abaloparatide and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Abaloparatide was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Abaloparatide was <NUM>µg/kg. In another group, Abaloparatide at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Abaloparatide was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Abaloparatide after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

Growth Hormone and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Growth Hormone was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Growth Hormone was <NUM>µg/kg. In another group, Growth Hormone at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Growth Hormone was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

The results showed that the blood concentration of Growth Hormone after the small-intestinal administration at <NUM>µg/kg was lower than the detection limit of ELISA. After addition of the composition of the present invention, the bioavailability of small-intestinal administration could reach <NUM>%.

Thymosin alpha-<NUM> and the composition of the present invention were mixed thoroughly in a weight ratio of <NUM>:<NUM>, and reserved for further use.

PK test for small-intestinal administration: Thymosin alpha-<NUM> was administered to fasted adult SD rats in a volume of <NUM>/kg via a small-intestine catheter, such that the dose of Thymosin alpha-<NUM> was <NUM>µg/kg. In another group, Thymosin alpha-<NUM> at <NUM>µg/kg together with the composition of the present invention was injected via a small-intestine catheter (ei), and blood samples were collected from tail vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

PK test for intravenous administration: Thymosin alpha-<NUM> was intravenously injected to fasted animals at <NUM>µg/kg, and blood samples were collected at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM>. The blood samples were anticoagulated with <NUM> EDTA and centrifuged at <NUM> at <NUM> rpm for <NUM>. The plasma was collected and subjected to quick freezing.

Claim 1:
A pharmaceutical composition for oral formulation, comprising a drug and an adjuvant, wherein the drug is polypeptide, insulin, or growth hormone; the adjuvant is composed of: a surfactant, an acrylic polymer, chitin or its derivatives, and a metal ion chelating agent; the surfactant is sodium lauryl sulfate, the acrylic polymer is carbomer, the chitin or its derivatives are chitosan, and the metal ion chelating agent is sodium citrate.