CN108721310B - Adriamycin and propranolol compound pharmaceutical composition and application thereof - Google Patents
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention belongs to the field of natural medicines, and discloses a compound pharmaceutical composition of adriamycin and propranolol and application thereof. The active ingredients of the compound pharmaceutical composition consist of adriamycin and propranolol in a molar ratio of 1:10-1: 200. The two combined medicines have stronger synergistic effect on treating the lymphoma.
Description
Technical Field
The invention belongs to the field of natural medicines, and particularly relates to a compound pharmaceutical composition of adriamycin and propranolol and application thereof.
Background
Cancer is a persistent disease that seriously harms human health and has now become the second leading killer to cardiovascular diseases. Since the 21 st century, the incidence of lymphoma has been increasing year by year due to the rapid progress of modern industrialization and the destruction of the immune system of lymphocytes caused by many factors such as environmental pollution, so that we have realized that the development of a pharmaceutical system for preventing and treating lymphoma is very urgent.
Doxorubicin (DOX) is an antitumor antibiotic, can inhibit the synthesis of RNA and DNA, has the strongest inhibition effect on RNA, has a wider antitumor spectrum, has an effect on various tumors, belongs to a cycle nonspecific medicine, and has a killing effect on tumor cells in various growth cycles. Is mainly suitable for acute leukemia, is effective for acute lymphocytic leukemia and granulocytic leukemia, and can be used as a second-line drug, namely, the drug can be considered to be applied when drug resistance is first selected. Malignant lymphoma, as the first drug to be used alternatively. Other cancers such as breast cancer, sarcoma, lung cancer, bladder cancer, etc. have certain curative effect, and are often used in combination with other anticancer drugs.
DOX plays a pivotal role in the treatment of malignant lymphoma and is currently widely used clinically despite its use history of over 60 years. In the clinical treatment of malignant lymphoma, the DOX needs to be used in large dose for long-term administration, and needs to be used under the monitoring of blood concentration due to large individual difference so as to ensure the safety of medication. DOX mainly acts on rapidly proliferating tumor cells and rapidly renewing cells, so common toxic and side effects of DOX include skin mucosa injury, bone marrow suppression, gastrointestinal reaction and hepatorenal toxicity. How to take DOX orally to take side effect and better exert anticancer effect is a medical problem which is very worthy of attention and research.
Propranolol (PROPRANOLOL, PRO) is an β -receptor blocker, can reduce myocardial contractility, autonomy, conductivity and excitability, slow heart rate, reduce cardiac output and myocardial oxygen consumption, can also be used for hyperthyroidism, can rapidly control tachycardia, tremor, body temperature rise and the like.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention mainly aims to provide a compound pharmaceutical composition of adriamycin and propranolol; the active ingredients of the compound pharmaceutical composition consist of adriamycin and propranolol.
The invention also aims to provide the application of the compound pharmaceutical composition; pharmacological tests prove that the compound pharmaceutical composition has a synergistic effect of resisting lymphoma.
The purpose of the invention is realized by the following technical scheme:
the compound medicine composition of adriamycin and propranolol has the active components of adriamycin and propranolol.
Preferably, the molar ratio of the adriamycin to the propranolol is 1:10-1: 200.
More preferably, the molar ratio of the adriamycin to the propranolol is 1:50-1: 100.
More preferably, the molar ratio of the adriamycin to the propranolol is 1: 100.
The compound pharmaceutical composition also contains a pharmaceutically acceptable carrier.
The compound pharmaceutical composition is prepared according to a conventional preparation process.
The application of the compound pharmaceutical composition of the adriamycin and the propranolol in preparing the anti-lymphoma drugs.
The above drugs can be used for the treatment of lymphoma in mammals including human.
Compared with the prior art, the invention has the following outstanding advantages and beneficial effects:
the inventor discovers that the combination administration of the adriamycin and the propranolol has good synergistic effect of anticancer cells when the adriamycin and the propranolol are combined and particularly matched according to the molar ratio of 1:50-1:100 in research on the compatibility pharmacological activity of the adriamycin and the propranolol; the inventor respectively carries out in-vitro MTT screening on Daudi, Raji and BC-3 as models, finds that the compounds have strong antiproliferative activity and show good relationship between time effect and dose effect, and combines the classical combined administration analysis Principle (media-effect Principle) and statistical analysis, the result shows that the compounds have synergistic effect, especially can obviously generate synergistic effect to inhibit the proliferation of three kinds of cancer cells when fa is less than 0.5, which shows that the DOX and propranolol composition can generate the biological effect of single dose of DOX or PRO when the low dose is compatible, thereby greatly reducing the toxic and side effect of the drugs and having good clinical medication development prospect; meanwhile, the equivalent dose evaluation shows that the toxicity of the compound medicament to the normal hepatocyte L-O2 is not increased.
Drawings
FIG. 1 is a graph of the safety assessment (apoptosis rate) of PBMC cells treated with DOX and PRO and optimized combinations of combinations for 72 hours.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
Example 1: screening and optimizing adriamycin (DOX) and Propranolol (PRO) compound pharmaceutical composition by adopting Daudi cells, Raji cells and BC-3 cells
Taking cells in logarithmic growth phase, inoculating 3 × 104Cells/well in 96-well plates, after 6 hours of growth, the supernatant was discarded by centrifugation and then administered in groups of: tumor cells are provided with no medicine adding group and medicine adding group, wherein the medicine adding group is provided with a DOX and PRO single medicine group and a DOX and PRO combined medicine group with different molar ratio groups, each group is provided with 4-6 multiple holes, the culture is carried out for 24 hours, the supernatant is discarded, 100 mul of MTT (tetrazolium salt) serum-free culture solution containing 0.5mg/ml is added for culture for 4 hours, 100 mul of DMSO (dimethyl sulfoxide) is added, the mixture is placed on a micro-oscillator for oscillation for 10min, and then the mixture is placed on an enzyme labeling instrument for detecting the OD value at 570 nm. Results the inhibition of tumor cell growth in each case was calculated according to the following inhibition formula, and the specific results are shown in table 1.
Inhibition rate (1-addition drug OD value/control group OD value)
Table 1 shows the IC at various concentrations of DOX and PRO administered alone and in combination to cells 72 hours after50The inhibition rate.
The inhibition of the combination of DOX and PRO in the molar ratio of 1:10-1:200, and the concentration of the combination of PRO in the molar ratio of 1:20, 1:50, 1:100 and 1:200 is increased. From the results, we can obtain that the inhibition rate is concentration-dependent with the increase of the compatible concentration. Wherein, the inhibition rate is found to be concentration-dependent with the increase of the compatible concentration.
TABLE 1 DOX & PRO single drug effect 72 hours IC50(μM)
Example 2: DOX and PRO combined drug effect analysis
Based on the Median-effect Principle (middle effect Principle or Chou-Talalay combined index method), Combidrug statistical software is used for drawing a dose-effect curve and a combination index curve (fa-C curve) under different effects, and the synergistic, antagonistic or additive relationship between the two medicines is quantitatively evaluated from the relationship between the effect of the combination of the two medicines and the combination index. The method comprises the following specific steps:
the drug effect, i.e. inhibition ratio (fa) ═ 1- (mean OD570 value of test group/mean OD570 of tumor cell blank control group) according to the equation of medium effect fa/fu ═ D/DmmTaking log fa/fu which is mlogD-mlogDm, setting a which is mlogDm, b which is m, X which is logD, y which is logfa/fu, substituting the formula of middle effect to obtain y which is bx-a, wherein fa is drug action effect, fu which is 1-fa, D is drug concentration, m is slope, and Dm is middle effect concentration, namely drug concentration at 50% effect, calculating the middle effect concentration Dm (logDm) 865-a/m of two anticancer drugs when used alone or in combination, calculating the drug concentration needed at various effects when used alone or in combination of two drugs [ D which is Dm (fa/f u)1/m ], calculating the combined use index of two drugs when used together (CI which is 58 1/DX1+ D2/DX 4) 1/m) when used alone or in combination of two drugs [ D which is DX/f u (DX/1/m), calculating the combined use index of two drugs when used together with two drugs [ CI) which is not DX 3, and No. DX 3 which is DX 3, and No. DX 3 is 6853, and No. DX is DX 3 when used alone or No. DX 3, and No. DX 3 is DX 3<1, the combined effect of the two medicines is synergistic; CI is 1, the combined effects of the two medicines are added; CI>1, the combination of the two medicines has antagonistic effect.
Through software analysis, the compound pharmaceutical composition has good synergistic effect, the specific effect is shown in table 2, and the compound pharmaceutical composition has strong synergistic effect (Very string synergy) according to the Principle of evaluating the effect by a Medium-effect prism, namely CI index is less than 0.1; strong synergy at CI indices of 0.1-0.3 (Strong synergy); CI index of 0.3-0.7 has synergistic effect (synergy); CI index of 0.7-0.85 has moderate synergistic effect (moderatesyntergism); the CI index is in the range of 0.85-0.90, and has weak synergistic effect (Slight synergy); the CI index is in the range of 0.90-1.10, and has a near additive effect (near additive); CI indices >1.10 and above have antagonistic effects.
As can be seen in Table 2, the combination of DOX and PRO has a synergistic effect; particularly, the synergistic effect is good when the two are matched in a molar ratio of 1-50:200, and the synergistic effect is strongest when the molar ratio of the two is 1: 100.
TABLE 2 CI comparison of combination index for DOX and PRO combinations of different combinations for 72 hours
Example 3: safety of DOX and PRO to peripheral blood mononuclear lymphocytes
After isolation and drug-culture of PBMC of mononuclear lymphocytes of healthy volunteers, safety of the PBMC with DOX and propranolol is evaluated (FIG. 1). ① fresh blood of healthy volunteers is extracted into a heparin anticoagulation tube (sterile), then the cells are resuspended (sterile) with an equal volume of PBS (or serum-free D-Hank buffer), ② the suspended cells are added into a pre-paved human lymphocyte separation liquid (preheated 37 ℃), the volume ratio of the lymphocyte separation liquid to the cell suspension is not lower than 1:1, ③ × g (or 2000rpm) horizontal centrifuge is centrifuged for 20-30min at room temperature (20-30 ℃), the supernatant is discarded at ④ ℃, an intermediate white mist layer is carefully aspirated into 5ml (or 1-2 times of volume) of PBS (or serum-free cell culture buffer), the supernatant is centrifuged at 200 rpm or 1000rpm for 10min at room temperature (20-30 ℃), the supernatant is discarded at 6335 ℃, the obtained precipitate is peripheral blood mononuclear lymphocytes (⑤), the PBMC is washed 2 times according to the operation, 6 g, the procedure, the supernatant is centrifuged at 200 rpm or 1000rpm for 10min, the room temperature (20-30 ℃) and the supernatant is collected by a flow-centrifugation method, the PPM centrifugation method, the supernatant is used for detecting the viable cell sedimentation rate of the PBMC is detected by adopting a slow cell precipitation method (365-50 mu) and the 20 mu cell precipitation method (365) and the detection method, wherein the detection is carried out by the detection scheme, the detection method, the detection of the No. 3625 mu detection is carried out at the No. 3625).
Example 4: the compound pharmaceutical composition of the adriamycin (DOX) and the Propranolol (PRO) is prepared into tablets according to the following prescription:
the prescription is as follows:
the preparation process comprises the following steps:
sieving the medicine and the auxiliary materials with a 80-mesh sieve respectively, fully mixing propranolol with 48 g of microcrystalline cellulose and 12 g of sodium carboxymethyl starch, preparing a soft material by 10% starch slurry, granulating with a 18-mesh sieve, and drying at 60 ℃ to obtain the granules 1. Fully mixing adriamycin with 24 g of microcrystalline cellulose, 15 g of starch and 8 g of sodium carboxymethyl starch, preparing a soft material by 10% starch slurry, granulating by using a 18-mesh sieve, and drying at 60 ℃ to obtain granules 2. And (3) fully mixing the granules 1 and 2 according to an equivalent increasing principle, finishing granules by a 16-mesh sieve, adding magnesium stearate, uniformly mixing, and tabletting to obtain 500mg tablets.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (4)
1. A compound pharmaceutical composition of adriamycin and propranolol with anti-lymphoma effect is characterized in that: the active ingredients of the compound pharmaceutical composition consist of adriamycin and propranolol; the molar ratio of the adriamycin to the propranolol is 1:50-1: 100.
2. The compound pharmaceutical composition of adriamycin and propranolol according to claim 1, which is characterized in that: the molar ratio of the adriamycin to the propranolol is 1: 100.
3. The compound pharmaceutical composition of adriamycin and propranolol according to claim 1, which is characterized in that: the compound pharmaceutical composition also contains a pharmaceutically acceptable carrier.
4. Use of the compound pharmaceutical composition of adriamycin and propranolol according to any one of claims 1 to 3 in preparation of anti-lymphoma drugs.
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