CN113546035A - Drug implant device having a cylindrical shape and a multi-part kit - Google Patents
Drug implant device having a cylindrical shape and a multi-part kit Download PDFInfo
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- CN113546035A CN113546035A CN202010427351.6A CN202010427351A CN113546035A CN 113546035 A CN113546035 A CN 113546035A CN 202010427351 A CN202010427351 A CN 202010427351A CN 113546035 A CN113546035 A CN 113546035A
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- 229940068204 drug implant Drugs 0.000 title claims abstract description 9
- 239000003844 drug implant Substances 0.000 title claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 229920000642 polymer Polymers 0.000 claims abstract description 20
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 12
- 239000007943 implant Substances 0.000 claims description 122
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 12
- 238000001727 in vivo Methods 0.000 claims description 7
- 230000036470 plasma concentration Effects 0.000 claims description 7
- 238000007920 subcutaneous administration Methods 0.000 claims description 7
- 239000011521 glass Substances 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
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- 206010033372 Pain and discomfort Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000007970 homogeneous dispersion Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 1
- RYOQQABIICMCBJ-UHFFFAOYSA-N C(COCC(=O)O)(=O)O.C(CO)(=O)O Chemical compound C(COCC(=O)O)(=O)O.C(CO)(=O)O RYOQQABIICMCBJ-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- UAHFGYDRQSXQEB-LEBBXHLNSA-N afamelanotide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 UAHFGYDRQSXQEB-LEBBXHLNSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229940065514 poly(lactide) Drugs 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 229940032159 propylene carbonate Drugs 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000004381 surface treatment Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
- A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Anesthesiology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Inorganic Chemistry (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a drug implant device having a cylindrical shape and a kit of parts. The drug implant device has a cylindrical shape and comprises a composition of an active pharmaceutical ingredient mixed with a polymer, wherein the composition further comprises water at a level of 0.5 to 4% by weight of the composition.
Description
Technical Field
The present invention relates to a drug implant device (drug implant device) having a cylindrical shape.
Background
The formulation and administration of implants is associated with a number of potential problems. The implant is not allowed to fragment or otherwise be damaged during administration. Pain and discomfort during and after the administration process are kept to a minimum. Once administered, the implant should be intact (and not accidentally break) so that the drug is released according to a predetermined release profile.
Disclosure of Invention
We have surprisingly found that one or more of the above or other problems can be overcome by using the implant of the present invention.
Thus, in one embodiment, the present invention relates to a pharmaceutical implant device having a cylindrical shape and comprising a composition of an active pharmaceutical ingredient mixed with a polymer, while it also preferably comprises water at a level of 0.5 to 4% by weight of the composition.
Preferably, the drug implant device has a diameter of 1.3 to 1.6mm and a length of 14 to 20 mm. Preferably, the implant device has a weight of 38mg to 40 mg. Preferably, the composition comprises 18mg afarnotide acetate and the polymer comprises poly (DL-lactide-co-glycolide). Preferably, the implant device has a density of 1.338mg/mm3To 1.40mg/mm3. Preferably, the implant device is an extruded implant. Preferably, the implant device is adapted for subcutaneous administration using a cannula. Preferably, the implant device is adapted to release alfanotide acetate in vivo at a plasma level of less than 10ng/ml for at least 24 hours.
In another embodiment, the invention relates to a composition having a concentration of 1.338mg/mm3To 1.400mg/mm3The density of implant of (1). Density represents the weight per volume unit of the implant. Preferably, the drug implant device has a cylindrical shape and comprises a composition of the active pharmaceutical ingredient mixed with a polymer, wherein the density of the implant is 1.338mg/mm3Up to 1.400mg/mm3。
Preferably, the device according to the invention, wherein the composition further comprises water at a level of 0.5 up to 4% by weight of the composition. Preferably, the device has a diameter of 1.3 to 1.6mm and a length of 14 to 19 mm. Preferably, the weight of the device is from 38mg to 42 mg. Preferably, the composition comprises 18mg of alfanotide acetate and the polymer comprises poly (DL-lactide-co-glycolide). Preferably, the implant is an extruded implant. Preferably, the implant is adapted for subcutaneous administration using a cannula. Preferably, the implant is adapted to release alfanotide acetate in vivo at a plasma level of less than 10ng/ml for at least 24 hours.
In another embodiment, the present invention relates to an implant device of a long, thin cylindrical shape that remains intact and does not fragment during administration, including all the details of the device as disclosed in the present invention. The device is adapted to remain intact when administered subcutaneously into the body. The device is preferably administered using a cannula device.
In other embodiments, the invention relates to a kit of parts comprising a pharmaceutical implant device in a glass container with a sealing lid. Preferably, the kit further comprises a cannula device for implant administration.
Without wishing to be bound by any theory, we believe that the inclusion of low levels of water in the implants of the invention provides benefits during administration. The inclusion of no or very low levels of water results in an implant that is brittle and may break during or immediately after administration, which would result in an undesirable, uncontrolled release profile. On the other hand, higher levels of water should be avoided as they result in an implant that will no longer retain its shape during or immediately after administration, which will also adversely affect drug release. Similarly, we believe that implant density is an important measure to ensure implant rigidity, and for subsequent release of drug in vivo as intended, the claimed density range enables the implant to withstand the pressure applied during subcutaneous administration of the implant. In addition, implants with higher densities are more densely packed, thereby reducing moisture absorption during storage. Furthermore, sealed storage helps to avoid exposure to moisture.
The elongated implant provides the following benefits: when the implant is applied, the opening in the skin for application may be small, alleviating pain and/or making it less likely that suturing of the skin is required. At the same time, the extended length of the elongated implant allows for the administration of sufficiently high amounts of drug, reduces the frequency of implant administration and/or allows for higher or greater amounts of drug plasma levels from one implant administration. The elongate implant according to the present invention preferably comprises a low level of water and/or a high weight per unit volume (density), providing optimal rigidity and flexibility of the elongate implant, allowing for effective administration (without fragmentation) through the skin of the subject and allowing for proper drug release in the subject.
The particular cannula device of the present invention allows for the effective administration of the elongate implant of the present invention through the skin of a subject.
Drawings
Fig. 1 schematically shows a preferred embodiment of an implant device according to the present invention.
Detailed Description
The present invention relates to specific implant devices comprising the compositions. The composition preferably comprises an active pharmaceutical ingredient and a polymeric material. Preferably, the active pharmaceutical ingredient is dispersed in the polymeric material, more preferably in the polymeric matrix.
Implant formulations are associated with a number of difficulties. In particular, the implant is not allowed to break or otherwise become damaged during (and preferably also immediately after) administration. Pain and discomfort during and after the administration process are kept to a minimum. It will be appreciated that immediately after administration, the implant will remain intact, however subsequently the implant will begin to release the drug and disintegrate, thereby providing the drug according to a predetermined release profile.
The implant of the present invention preferably has a cylindrical shape and is preferably elongate. In particular, the implant preferably has a diameter "D" of at least 1.3mm, more preferably at least 1.4mm, and preferably at most 1.6mm and more preferably at most 1.5 mm. Preferably, the implant has a length "L" of at least 14mm, more preferably at least 15mm and preferably at most 20mm and more preferably at most 19 mm. According to the invention, 3.14 can be used for pi.
Such an elongated cylindrically shaped implant allows for easy and good administration with few complications for the patient and the medical staff, providing a preferred release profile, but requiring a specific formulation according to the invention.
In addition to its shape, we have surprisingly found that the integrity of the implant is also due to the rigidity provided by the implant components.
In particular, we have surprisingly found that the inclusion of low levels of water in the composition of the implant results in good administration characteristics of the implant.
In another embodiment of the invention we have found that the implant preferably has a density as defined herein.
Although the polymers of the present invention are expected to be susceptible to hydrolysis and decomposition under the influence of water, thereby adversely affecting the integrity of the implant prior to administration, we have surprisingly found that low levels of water in the implants of the present invention do not result in adverse effects. However, these low levels of water provide beneficial properties to the implant, allowing for optimal administration of long, thin cylindrical shaped implants. We have found that low levels of water allow the implant to retain its shape during and immediately after administration so that the implant does not break or drug release is impaired in some way. After administration, the implant will release the drug and will slowly degrade in vivo as expected.
Thus, the present invention preferably relates to an implant having a composition comprising water preferably at a level of at least 0.5%, more preferably at least 1%, most preferably at least 1.5%, particularly preferably at a level of more than 2% and preferably at most 4%, more preferably at most 3.5%. The level of water in the implant can be determined using standard procedures well known in the art and to the skilled person. An example of a preferred method that can be used in the present invention is Karl fischer (Karl Fisher) titration.
Preferably, the active pharmaceutical ingredient is an alfanotide, also known as melanotan i (melanton i) and [ Nle [ ]4,D-Phe7]- α -MSH. Preferably, the acetate salt of alfarnosine is contained in the implant device. Preferably, the alfanotide is present in the implant as acetate and preferably at a level of 18mg calculated as acetate.
Preferably, the polymer is a biodegradable polymer. Preferably, the polymeric material is prepared from monomer units selected from lactic acid and/or glycolic acid (diglycolic acid). Preferred polymers for use in the implants of the present invention are selected from the group consisting of poly (lactide), poly (glycolide), poly (lactide-co-glycolide), and mixtures thereof. Preferred polymers comprise poly (lactide-co-glycolide) and preferably poly (DL-lactide-co-glycolide). Most preferably, the polymer is poly (DL-lactide-co-glycolide). The polymer is present in the implant at a level of preferably at least 15.3mg and preferably at most 19.5 mg.
Preferably, the active pharmaceutical ingredient is mixed with the polymer, preferably resulting in a homogeneous dispersion of the active ingredient in the polymer matrix. Preferably, the water is dispersed in the polymer matrix, preferably homogeneously. Preferably, the active ingredient and water are a homogeneous dispersion of the polymer matrix.
The composition of the implant may also comprise optional pharmaceutically acceptable ingredients. Obviously, all the components of the implant together constitute 100% by weight of the implant.
Preferably, the total weight of the implant is at least 37.6mg, more preferably at least 38mg, and preferably at most 42mg and more preferably at most 41mg, most preferably at most 40mg and particularly preferably at most 39 mg.
The implant preferably has a thickness of 1.338mg/mm3More preferably 1.340mg/mm3Most preferably 1.345/mm3And preferably up to 1.400mg/mm3More preferably up to 1.390mg/mm3Most preferably up to 1.360mg/mm3And particularly preferably up to 1.355mg/mm3The density of (c).
Preferably, the implants of the present invention are prepared by extruding a mixture of the components through an extrusion die having an appropriate diameter and then cutting the extrudate into appropriate lengths according to the present invention. Thus, the present invention preferably relates to an extruded implant having a diameter and length as shown herein.
The implant of the invention is preferably suitable for subcutaneous administration, preferably for use by a cannula, more preferably an SFM implantation cannula. Preferably, the cannula device is combined with the implant device in a multi-part kit. The cannula device has an internal opening, preferably comprising a piston, having an outer diameter allowing movement (i.e. insertion and/or withdrawal) in the internal open space of the cannula device. The inner opening of the cannula device preferably has an inner diameter in which the elongated implant is feasible to be placed. Preferably, the cannula can include the elongate implant device with minimal (or preferably no) additional space so that the elongate implant device can slide along the interior of the cannula. Preferably, the cannula further has a length sufficient to contain a long implant device. Sufficient rigidity and flexibility of the implant (due to the low level of water and/or high density according to the present invention) allows the use of a piston to push the implant out of the cannula below the skin.
The implant of the invention is preferably adapted to release alfanotide acetate according to a preferred release profile, preferably maintained at plasma levels of less than 10ng/ml for at least 24 hours.
In other embodiments, the invention relates to a multi-part kit containing an implant in a glass container with a sealing lid. Preferably, the kit further comprises a cannula device for implant administration. The sealed container allows the implant to be protected against moisture. This ensures that the implant maintains the water level as shown herein. Preferably, the sealed container is a vial with a rubber stopper.
Fig. 1 schematically shows an implant device of the present invention having a composition comprising an active pharmaceutical ingredient dispersed in a polymer composition, as shown at end 2 of the implant. The cylindrically shaped implant has a diameter D as shown at the bottom of the figure and the cylindrical shell (mantle) 1 has a length L. The cylindrical implant is elongate. The composition of the implant preferably comprises water at a level of 0.5-4% by weight of the composition.
As shown in fig. 1, the cylindrical implant has a shell 1 and two ends 2. In a preferred embodiment, the surface of the shell of the cylindrical implant is solvent treated. Preferably, at most one of the ends of the cylindrical implant is solvent treated, while at least one end is not solvent treated. In one embodiment, one end of the cylindrical implant is not solvent treated, while the other is solvent treated. In another embodiment, both ends of the cylindrical implant are not solvent treated. Preferably, the surface of at least one end (preferably both ends) of the cylindrical implant has a visually different morphology than the surface of the shell. Treating the implant surface means contacting the surface with a solvent, for example by dipping or by spraying. Examples of solvents are ethanol, water, ethyl acetate, dichloromethane, chloroform, acetone, anisole and mixtures thereof. Other options include methyl acetate, N-methyl-2-pyrrolidone, isopropanol, tetrahydrofuran, dimethyl sulfoxide, 2-pyrrolidone, triethyl citrate, ethyl lactate, propylene carbonate, benzyl alcohol, benzyl benzoate, supercritical carbon dioxide, acetonitrile, or mixtures of any of the above mentioned solvents. The surface treatment affects the morphology (visible features) of the surface area. Without wishing to be bound by any theory, it is believed that the solvent treatment may inactivate the active pharmaceutical ingredient on the surface, while the active pharmaceutical ingredient may still be initially released from the surface without the solvent treatment.
The following examples are illustrative of the invention and are not intended to be limiting.
Examples
Example 1
Different batches of implants were extruded from a composition comprising 18mg of alfasin acetate in admixture with water and poly (DL-lactide-co-glycolide). For each batch, the extrudate was cut to produce implants according to the invention having a length of about 1.7 cm. The diameters and water levels are shown below. The water level was confirmed using standard karl fischer titration.
Batch 3 had a diameter of 1.45mm and contained 3.2% by weight of water.
Batch 4 had a diameter of 1.44mm and contained 3.1% by weight of water.
Batch 5 had a diameter of 1.46mm and contained 3.4% by weight of water.
The implants exhibit excellent in vitro release within specifications and consistent with a predetermined release. During the subcutaneous administration of the in vivo procedure, the implant remains intact. In contrast, implants with no or very low levels of water are more fragile and can be easily broken during administration or immediately after introduction into the body. Implants with higher levels of water do not retain their proper shape during and after administration. The conclusion is as follows: the use of no/low and high levels of water results in an implant that is not preferred for administration to a subject.
Example 2
A composition comprising a homogeneous mixture of 18mg of alfasin, poly (DL-lactide-co-glycolide) and 0.5-4% by weight of water was extruded and cut into long, thin cylindrical implants having the following characteristics:
the density of the implant of batch A was 1.349mg/mm3(weight 38.3mg, diameter 1.45mm and length 17.2mm, and pi [ pi ] pi]Use 3.14).
The density of the implant of batch B was 1.352mg/mm3(weight 38.9mg, diameter 1.46mm and length 17.2 mm).
The implants of batches a and B had the preferred implant density and showed good application characteristics.
Example 3
The implants of batches 1, 2, 3, 4 and 5 and batches a and B were successfully administered subcutaneously in human subjects using a cannula device with a piston and features as described herein, resulting in preferred plasma levels as indicated.
Claims (18)
1. A pharmaceutical implant device having a cylindrical shape and comprising a composition of an active pharmaceutical ingredient mixed with a polymer, wherein the composition further comprises water at a level of 0.5 to 4% by weight of the composition.
2. The device of claim 1, wherein the device has a diameter of 1.3 to 1.6mm and a length of 14 to 20 mm.
3. The device of any one of claims 1-2, having a weight of 38mg to 40 mg.
4. The device of any one of claims 1-3, wherein the composition comprises 18mg of alfanotide acetate and the polymer comprises poly (DL-lactide-co-glycolide).
5. The device of any of claims 1-4, wherein the implant has 1.338mg/mm3To 1.40mg/mm3The density of (c).
6. The device of any one of claims 1-5, wherein the implant is an extruded implant.
7. The device of any one of claims 1-6, wherein the implant is adapted for subcutaneous administration using a cannula.
8. The device of any one of claims 1-7, wherein the implant is adapted to release alfanotide acetate in vivo for at least 24 hours at a plasma level of less than 10 ng/ml.
9. A pharmaceutical implant device having a cylindrical shape and comprising a composition of an active pharmaceutical ingredient mixed with a polymer, wherein the implant has 1.338mg/mm3Up to 1.400mg/mm3The density of (c).
10. The device of claim 9, wherein the composition further comprises water at a level of 0.5 up to 4% by weight of the composition.
11. The device of any of claims 9-10, wherein the device has a diameter of 1.3 to 1.6mm and a length of 14 to 19 mm.
12. The device of any one of claims 9-11, having a weight of 38mg to 42 mg.
13. The device of any one of claims 9-12, wherein the composition comprises 18mg alfanotide acetate and the polymer comprises poly (DL-lactide-co-glycolide).
14. The apparatus of any one of claims 9-13, wherein the implant is an extruded implant.
15. The apparatus of any one of claims 9-14, wherein the implant is adapted for subcutaneous administration using a cannula.
16. The device of any one of claims 9-15, wherein the implant is adapted to release alfanotide acetate in vivo for at least 24 hours at a plasma level of less than 10 ng/ml.
17. A multi-part kit containing a drug implant device in a glass container with a sealing lid.
18. The kit of claim 17, further comprising a cannula device.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP20171218 | 2020-04-23 | ||
| EP20171218.9 | 2020-04-23 |
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| Publication Number | Publication Date |
|---|---|
| CN113546035A true CN113546035A (en) | 2021-10-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202020845236.6U Expired - Fee Related CN214181164U (en) | 2020-04-23 | 2020-05-19 | Drug implant device and multi-part kit |
| CN202010427351.6A Pending CN113546035A (en) | 2020-04-23 | 2020-05-19 | Drug implant device having a cylindrical shape and a multi-part kit |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202020845236.6U Expired - Fee Related CN214181164U (en) | 2020-04-23 | 2020-05-19 | Drug implant device and multi-part kit |
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| Country | Link |
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| CN (2) | CN214181164U (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060029678A1 (en) * | 2003-03-01 | 2006-02-09 | Romano Deghenghi | Process for the production of implants |
| CN1812771A (en) * | 2003-06-26 | 2006-08-02 | 梅迪奥拉努姆制药有限公司 | Subcutaneous implants having limited initial release of the active principle and subsequent linearly varying extended release thereof |
| US20080305152A1 (en) * | 2004-08-04 | 2008-12-11 | Clinuvel Pharmaceuticals Limited | Methods of Inducing Melanogenesis in a Subject |
| WO2015063099A1 (en) * | 2013-10-28 | 2015-05-07 | Clinuvel Ag | Alpha-msh analogues for use in the treatment of hailey-hailey disease |
-
2020
- 2020-05-19 CN CN202020845236.6U patent/CN214181164U/en not_active Expired - Fee Related
- 2020-05-19 CN CN202010427351.6A patent/CN113546035A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060029678A1 (en) * | 2003-03-01 | 2006-02-09 | Romano Deghenghi | Process for the production of implants |
| CN1812771A (en) * | 2003-06-26 | 2006-08-02 | 梅迪奥拉努姆制药有限公司 | Subcutaneous implants having limited initial release of the active principle and subsequent linearly varying extended release thereof |
| US20080305152A1 (en) * | 2004-08-04 | 2008-12-11 | Clinuvel Pharmaceuticals Limited | Methods of Inducing Melanogenesis in a Subject |
| WO2015063099A1 (en) * | 2013-10-28 | 2015-05-07 | Clinuvel Ag | Alpha-msh analogues for use in the treatment of hailey-hailey disease |
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|---|---|
| CN214181164U (en) | 2021-09-14 |
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