JPS60256467A - Medical drug administration method and means - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION The present invention relates generally to the field of surgical device research, and more particularly to improvements in methods and means for the administration of solid medicaments in subcutaneous dosing and the manufacture of medicaments.

BACKGROUND OF THE INVENTION Although most subcutaneous medications involve the use of axillary drugs injected through a syringe, treatments may require the introduction of small amounts of drug into the bloodstream over a period of time. This need is best met by the use of drugs in the form of solid pellets with an outer surface that gradually dissolves and enters the bloodstream.

A typical example of this method is the treatment of menopausal estrogen deficiency in women by injecting small pills of 17beta to estradiol. This supplementation has major health benefits.

In the known method, the injection is a compressed cylindrical pellet containing 1 g of 17 beta estradiol 25II without any excipients. This small pill has a diameter of approximately 3.2 mm and a length of approximately 3 mm.
．． It is 5mm. Injection is performed using an intubation equipped with two puncture needles with the same internal diameter as the diameter of the pellet (3.2 mm). The first puncture needle has a sharp tip for introducing the intubation, and the second puncture needle has a blunt tip for subsequently inserting the pill. A small amount of anesthesia is injected under the skin, and then a small incision is made in the skin with a sharp scalpel blade. Through this incision, an intubation with a sharp puncture needle is inserted several centimeters into the subcutaneous fat, approximately parallel to the skin, after which an injectable pill is inserted into the intubation and pushed through it using a blunt puncture needle, and then The intubation is retrieved. One or two stitches may be needed to close the incision. Experienced doctors J and I can perform this procedure twice.
Although it can be completed in ~3 minutes, the intubation and puncture needles must be disinfected before each use, and this procedure is not considered adequate. Furthermore, because the known small pills have the above dimensions,
Continuous dosing of estrogen lasts approximately 3 months.

For optimal therapeutic effect for women who require estrogen replacement, small doses of estradiol are administered once daily for 3 to 4 weeks every 5 to 7 days, and currently the use of oral medications. followed by the last l of estrogen treatment
Many doctors add small doses of the "opposite" prosestin for 0 to 12 days. Studies have shown that oral administration exposes the liver to counterintuitive high doses of estrogen, resulting in alterations in liver protein synthesis and increasing a variety of negative outcomes, including: It is becoming °. These include high blood pressure, increased blood clotting (phlebitis, cerebral thrombosis, cerebral thrombosis), changes in blood glycolipids (possible increased risk of coronary artery disease), and risk of benign vascular tumors in the liver itself.

As discussed in detail above, other parenteral methods for delivering estrogen directly to the systemic circulation result in prolonged unopposed continuous exposure to estrogen. It has been found that continuous unopposed exposure to such estrogens, whether administered orally or parenterally, results in an increased risk of uterine cancer. Therefore, the ideal method is 3
Lasting for ~4 weeks, it is a convenient, painless method of administering progestin to allow intrauterine maturation, and is repeatable monthly for most patients. Another parenteral method uses intramuscular injection of estradiol in oil to create temporarily high estrogen levels that decrease more slowly than expected, but are also very painful. The invention described herein obviates the drawbacks and side effects of such supplemental treatments.

Devices for subcutaneous injection of small pills are known in veterinary medicine. One of the devices is Kerkutz's August 8, 1878,
No.4. -105,030. Outside of Fruen and Al, July 23, 1880, ITh 4
．． 223.674. While useful in the veterinary field, such devices are not suitable for use with human patients. The devices disclosed in these patents allow for the use of needles with a diameter of 2.7 to 4.0 mm and a length of 80 to 90 mm. Such large needles are unbearably painful for normal human use. On the other hand, both prior art devices are not equipped to handle thin disposable needles.

The abutment or obturator portion of these devices does not accommodate small needles or

There is no complicated mechanism for correctly withdrawing the needle function with a thin obturator without folding or bending.

More importantly, prior art devices allow for pellet dimensions of 2.5-3.5 mm in diameter. Injectable pellets of such size would cause unacceptably large injuries to the patient.

Most importantly, both prior art devices are in some ways not sufficiently sterile for human use. In Kerkutz's device, there is a front needle guide that contacts the barrel of the needle before dispensing. Fluen and Al's device requires a groove on the needle cylinder for an exchangeable set screw;
There is a risk of contamination each time the sword is replaced. Both instructions describe the use of a cartridge, but do not teach the construction of the unit, which includes the needle, pellets, and sterile disposable obturator. Fluen and Al press a device against the patient to retrieve the needle, something that would be impossible for a human patient. Kerkutz used a spring to retrieve the needle, but this method is also applicable only to veterinary medicine. Neither explanation is suitable for use as a device for humans.

SUMMARY OF THE INVENTION The present invention provides a subcutaneously applied extended pharmaceutical pellet comprising a hollow cylinder incorporating a sliding portion with means for securing the needle to the end; It includes a hollow needle into which the pellet to be injected is placed and an obturator whose length is slightly larger than the length of the needle. In use, the cartridge portion engages the guide portion at one end thereof. The free end of the needle is inserted into the patient's subcutaneous fat and the slide moves in the opposite direction to retrieve the needle into the hollow cylinder. During this movement, the obturator remains mutually stationary with one end thereof engaging the receiving surface of the guide and the opposite end of the obturator engaging one end of the pellet, so that the needle is withdrawn. Then, the pill remains at the injection site. Synthetic pellets having a center formed by a first component and a periphery formed by a second component are simultaneously described, i.e. a center that does not undergo chemical change upon dissolution having the first and second components. This is a method for manufacturing small pills using

SUMMARY OF THE INVENTION Briefly, the present invention provides an improved device for subcutaneously injecting solid extended synthetic pellets that is somewhat similar to dispensing liquid drugs using a conventional hypodermic syringe. . The device includes a hollow cylinder slidably mounted at its distal end with a pair of arms having cartridges engaged with the ends. The closed, sterile, disposable cartridge portion has a hollow needle at its base or hub with means for engaging the distal end. A cylindrical pellet is placed within the needle and a blunt obturator extends from the base of the needle. After subcutaneous insertion, the needle is retrieved when the guide arm is moved outward within the cylinder. Since the obturator remains fixed, retrieval of the button holds the pill exposed at the injection site. After injection of the pellets, the cartridge part is discarded. There are two types of this pill. Pure estradiol pellets provide only etrogen and are replenished at the end of the cycle by oral dosing of brozestin. Another type contains a 0.2 mm core of a progesterone estradiol mixture that releases prosestin during the last third of the cycle. The exact dimensions of the core and the mixing ratio will vary depending on individual requirements.

In the preferred method of making pellets, the most advantageous form is one having a core of a biologically inert, biodegradable polymer such as polygraftine, polylactone, polylactide, etc. these are,
The material from which synthetic, easily absorbable suture threads are commonly manufactured, with a thin layer of active pharmaceutical agents such as estrogens, estrogen-prosestogens, hormone antagonists, or other agents described in the co-filed application. coated with. Generally, small pills are 15 to 25 mm long and 0.04 mm in diameter.
~0. [It is 18 mm. There are many ways to manufacture pellets. The center of the fiber is immersed in an estradiol solution and pulled up through a mold, and coated with the desired thickness by dipping, or the estradiol in a volatile solvent is made into a fine spray under pressure and placed in a rotating am. Spray to coat.

The advantage of using a coated, chemically unchanged fiber core is that continuous coatings of various synthetic solutions can be applied by dipping or spraying.
It is easy to manufacture layered pellets, and the change in surface area due to absorption from the onset of absorption to the complete dissolution of the drug is very small, approximately less than 10%, which means that the entire duration of action of the pellet is very small. The drug supply rate is kept almost constant during the period, and the effect is quickly blocked at the end.

DETAILED DESCRIPTION OF THE EMBODIMENTS A device according to the invention is designated generally by the reference numeral 10 and generally includes a guide portion 11, a disposable needle cartridge portion 12 containing pellets.
Consists of.

The guide 11 is preferably reusable and formed of metal construction. It comprises a hollow elongated cylinder 16, a first end 17 provided with a finger grip 18 on the outer surface 19. The removable (threaded) end wall or cap 20 includes a centrally located inward projection 21 forming a receiving surface and first and second passage openings 22,23. The second end 24 is partially closed by a wall 25 having a centrally located opening 26 . Within the cylinder 16 is a slide 30, a first end 31 having a manually engaged grip 32 carried on the ends of first and second extension arms 33.34 passing through the apertures 22.23, respectively. is placed. Arm 3
The opposite ends of 3 and 34 support a centrally located recess 38 and a cartridge engagement means 38 in the form of a hook or bayonet for quick installation. The deformation means (not shown) consist of a single threaded engagement.

Cartridge part 12 includes a hollow needle part 40 with a sharp tip 41 and a second end 42 including a hub 43 with engagement means matching means 38 . Obturator 44 includes a second end 46 extending into the base of needle 40 at first ends 45 and 47 that engage abutment surface 21 .

The pellet 15 contains estradiol amg and has a diameter of 0.8 mm, which coincides with the needle hole, and a length of 20+*m. The diameter center contains 0.2 mm of the proesterone/estradiol mixture, a drug that releases prosestin during the last third of the cycle, and this center is surrounded by pure estradiol with an external diameter of 0.4 m+n. A pill of this size is calculated to provide normal physiological levels of estradiol for 3-4 weeks before complete absorption. Adjustment of exact dimensions and progesterone content requires appropriate experimentation.

The dosing of the pellets will become clear upon consideration of the drawings. To conveniently assemble the device, the threaded end wall 20 or cap is first removed from the cylinder 1B along with the sliding arms 33-34 and cylinder-lock 37. The disposable cartridge 12 is then attached to the cylinder-lock 37 and the obturator 44 is passed through the cylinder to the free end 15 within the receiving surface 21 of the cap 20.
Stop at . The cartridge then moves down the cylinder 16 through the central opening 28 and the cap is screwed back into the cylinder 18. FIG. 2 shows the device 10 assembled with a needle inserted into the subcutaneous fat of a patient. At this point the pill is positioned at the desired injection location and the device is then removed leaving the guide 11 in the position shown.
When the sliding grip 32 is moved outwardly while holding the obturator 44, the needle portion 40 is retrieved while the obturator 44 remains in that position. As a result, the pill is exposed and the slide 30 is progressively exposed until it reaches its outermost position, at which point the end 4G of the obturator passes the free end of the needle. The pellet is completely released in this position and the device is easily removed.

A fully disposable device as requested would remove the guide and place a manual engagement means on the rather large hub of the cartridge which would be handled by the index and middle fingers, and the outer end of the obturator would have means for engaging the thumb.1. , It's okay to be given. In this case, the index finger means is provided with means on the outer surface of the obturator to indicate that the needle has been completely withdrawn.

As previously mentioned, the preferred form of the pellet contains a biodegradable polymeric core that does not undergo chemical changes, and is the form shown in FIGS. 7 and 8. What is shown in FIG. 7 is a small pill of estradiol, which is drawn to show a longitudinal section and a transverse section. In this small pill,
The center diameter is 0.60 mm and the estradiol layer is 0.60 mm.
It is 0.025mm thick. FIG. 8 shows a similar pill for sequential dosing of first pure estradiol and then estradiol-prosestogen mixture to induce a simulated menstrual cycle. Approximately 1 pill per day for approximately 21 to 23 days for both small pills
00 micrograms of estradiol. The pill shown in Figure 8 additionally provides about 50 micrograms of norzestrel per day for the last 10-12 days of the cycle. Preliminary experiments showed that the concentration of the estradiol layer was about 2 mg/mrr1', and its □□4o~50mrn, ka, 8°. 1,1o 1・(
□〈It turned out to be something. The pill shown in Figure 7 has an initial surface area of 45 mm' and a final surface area (
The last absorbed layer of estradiol is approximately 43 mr.
It is n'. This contains approximately 2.2 mg of estradiol.

There are many ways to make small pills. The center of the fiber is immersed in an estradiol solution, pulled out through a mold while still hot to solidify its outer shape, and dipped repeatedly in an estradiol solution and volatile solvent until a film of the desired thickness is formed.
Alternatively, a fine spray of estradiol in a volatile solvent under pressure is applied to the rotating fibers. It is best to feed the core from the source to the processing area and allow it to dry or harden on a storage shaft, followed by rolling up the treated core. The pellets are made into various lengths according to the various strengths of medicinal efficacy, preferably by cutting the series to the desired length using mechanical equipment.

This application also calls for the dosing of small pills as peptide contraceptive agents. LHRH (Luliverine) is a 16-amino peptide (decapeptide) that is released from the hypothalamus and is a sugar protein (hormone) that stimulates the sex hormone glands.
Luteinizing hormone (LH), follicle stimulating hormone (FSH)
), which in turn stimulates the pituitary gland, which secretes hormones, and adjusts the functions of the ovaries and hemispheres one after another, causing the production of sex hormones, eggs, and sperm.

As a result of recent research, it has been found that D-amino acids, which are similar to LHRH, suppress the secretion of FSH and LH from the pituitary gland. Of particular interest are those analogs that exhibit potent LHRH antagonist activity. These peptides can be used in a variety of medical conditions because they induce a state of severe (or ovarian) hyposecretion (i.e., inactivity of the hemispheres and ovaries) and the opposite reaction when administration of the material is discontinued. This makes it possible to use pharmacological drugs that can be used in a variety of ways, which is a desirable situation.

For example, conditions such as prostate cancer, breast cancer, female contraceptives, male contraceptives, ectopic development of endometrial tissue, and premature sexual maturation.

The above treatment methods are already known in the art. However, no suitable method for administering these peptides to humans has been discovered. Since these drugs easily destroy gastrointestinal tissues, active oral administration has not been carried out. Accurate long-term metered parenteral dosing systems are highly required.

Ideally, injections are given once a week, once a month, or more frequently. These contents are 10~ per day
The coated cylindrical pellets in the fine needle cartridge of the present invention are ideal because as little as 15 micrograms are effective. Relatively insoluble analogues whose characteristics have been published and studied (e.g. NAc-IA 1 a (1
) -para chloro -dPhe (2)
-dTryP(3,6) LHRH).

A suitable treatment is calculated to release 50 micrograms of drug per day for 30 days from the surface area 'lj''*T
I MJ un'8 # ;15! ＃W (7)
k'J 1-5 mg t7) a (II $ v
Including providing coated pellets. To be used for contraception, this drug must be supplemented because it suppresses normal sex steroid hormone production as well as gamete development. In women, this is done by giving the estrogen-prosestogen pellets in parallel at the same time, and the LHRH-like pellets can be injected with the same needle. For men, an alternative method is to give them testrogens.

The advantage of this contraceptive system is that it eliminates the need to remember to take oral contraceptives every day, and compared to the large doses required for contraceptives, LHRH
The analog is a practical contraceptive, and since it is parenteral, only physiological doses of steroids are given, avoiding the side effects on the liver caused by large doses of steroids. Use of the potion does not cause the harmful side effects such as hypertension, frevitis, or coronary thrombosis associated with perspective control buildings such as Emporism.

4. Ka. , A4, and B, reference numbers in the specification are used to indicate the same parts of the drawings.

FIG. 1 is a perspective side view with portions removed to show details of an embodiment of the invention with the disposable needle cartridge removed.

FIG. 2 is a central longitudinal section with the needle cartridge installed and the device in its 'ready' or pre-injection configuration.

FIG. 3 is a center cross-sectional view of the needle cartridge section in a separated state.

FIG. 4 is a central vertical cross-sectional view of the small pill.

FIG. 5 is a front view of the end of the small pill shown in FIG. 4.

FIG. 6 is a central longitudinal cross-sectional view showing the device in the "discharged" or post-injection configuration with the needle cartridge installed.

FIG. 7 is a partially cut away schematic diagram of a first variant of the pellet.

FIG. 8 is a similar diagram showing a second variant of the pellet.

10. Device of the present invention, 11. Guide portion, 13. Small pill, 15. Free end, 16. Cylinder, 170. first end, 1
80. Grip, 190. Outer surface, 201111 Cap, 21...Receiving surface, 22.23.Fist opening, 24..Second end, 2511.Wall, 26..Opening, 30..Sliding part, 3
111・First end, 32・Grip, 33.34・Arm, 37・Cylinder lock, 381+・Recessed part,
39...Engagement means, 4o...Needle portion, 42・Second end, 4
3. Hub, 44. Obturator, 45. First end, No. 46. Second end.

patent applicant Nice Mitchell battle barman agent Of the drawings! 'f咄 (changes in content) Procedural amendment (formality) %formula% , incident display Methods and means of medical medication , person who makes corrections Relationship to the incident: Patent applicant Name: Niss°Mitschel°Berman , Agent〒101 Target figure for correction , content of correction We will submit appropriate drawings (all drawings) in accordance with your instructions.

Claims (1)

[Scope of Claims] ■ An extended fixing guide part including a first interfixing part and a second part slidably associated with the first part, the second part having a means for engaging the hand and a receiving surface part thereon; a second part having a first and second end, the second part having a first free end, the second part having a cartridge engagement means, the first free end; a single-use extended disposable cartridge comprising a hollow needle portion having a second end having a hub; a hub having a coupling means, an extended drug-containing pellet slidably disposed within the needle, an extended obturator longer than the needle, initially slidably disposed within the second end of the needle; the obturator having a first end, a second end that does not intercommunicate with the first part and abuts the receiving surface of the first part, thereby effecting subcutaneous insertion of the free end of the needle; the obturator, in which the agent is placed within the patient's body, and which prevents movement of the pill by moving the second part in a given direction relative to the first part to retrieve the beam; A device for subcutaneous injection of solid pellets comprising said cartridge containing said obturator which is disposable after one use. further characterizing the first part having a second part having a hollow cylinder and including a first end in a seven-annular grime and a second end in a cylinder having needle cartridge engagement means; An apparatus according to claim 1. ■ As a new article of manufacture, a hollow needle having a first free end and a second end abutting the hub, an extended pill of diameter corresponding to the inner diameter of the needle and slidably disposed therein;
an obturator initially partially disposed within said needle and having an effective length slightly greater than the length of said needle, whereby said needle expels said pill and means for securing said obturator associated therewith; A single-use, disposable needle portion for the subcutaneous injection of drug-containing pellets comprising a hub having mating engagement means.