JPS58501226A - Methods for preparing and using intravenous nutritional compositions - 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] Method of preparing and using intravenous nutritional composition Background of the invention 1. Field of invention The present invention 1 relates to a method for making and using a nutritional composition for parenteral administration. .

More specifically, the present invention is suitable for intravenous administration to mammals after adding water. method for the preparation and use of stable, dry-packaged, sterile nutritional compositions containing Ru.

2. Brief explanation of conventional technology Conventionally available parenteral nutritional compositions require highly complex and expensive manufacturing processes. It was generally made in the form of an aqueous solution using field equipment. Because of these costs, this These facilities are small in number and located far away from many locations where the solution needs to be used. is in

Therefore, transporting aqueous solutions to distant locations of use, such as hospitals, clinics and medical facilities, Additional costs arise from the need to do so.

The need for centralized and expensive equipment to make parenteral nutritional compositions preparation for use, i.e., meeting strict requirements for parenteral administration to humans. The need for preparation in the form of a corresponding aqueous solution is specified.

This need has increased in recent years to ensure that sterile, non-pyrogenic and This has resulted from increasingly stringent standards for the absence of foreign particulate matter.

In fact, the standards currently in place are actually just as complex and sophisticated as they are described above. high levels previously achievable economically only with expensive factory equipment. Ru.

There are numerous obvious problems associated with traditional systems for delivering parenteral nutritional compositions where they are used. There are other and less obvious drawbacks.

Most obvious disadvantage: d. Storage of bulky and heavy water, the main component of this parenteral solution. and must be transported. Traditionally, dried for transport to point of use It has been proposed to make nutritional compositions in packaged form; for example, US Pat. See 4B 697. Forms solution at point of use and saves large amounts of water storage and transport Sterile water is mixed with the dry composition at the point of use to ensure cleanliness. Unfortunately, extraintestinal Proposals to package and transport compositions in dry form have not been commercially successful.

One of the main reasons for failure is sterility, nonpyrogenicity and the absence of particulate matter. It is not possible to create an aqueous solution from a dry form at the point of use that meets the exacting requirements of It is to be.

This, in part, requires that the dry nutrient composition be self-contained in a state of acceptable sterility and purity. Depends on the lack of a way to build the body.

Even if sterile, pyrogen-free water is used for mixing with the dry form of the nutrient composition, Even if available at commercial locations, the product after mixing is generally unsatisfactory. and does not meet the criteria.

According to the method of our invention, a stable, dry packaged, sterile, pyrogen It will provide a nutritional solution with 11 compositions containing no nutrients.

In addition, the method of the invention includes sterilization of parenteral nutritional solutions by autoclaving. eliminates many other intermediate molds associated with traditional systems.

Parenteral solution 1 is packaged and then autoclaved to ensure sterility. will be attached.

Autoclaving as a sterilization method is the process of sterilization of nutrient substances under autoclave conditions. Because of the chemical reactivity (C1), it is assumed that only the type of nutrients present in the solution during sterilization forgive. For example, amino acids and reduced dextrose, for example, mylar (Ma ilLard) are combined in a reaction to create an AIadOri compound. This is potentially It is highly toxic and almost impossible to use, especially when injected intravenously. Conventional method Another example of the limitations created by autoclave sterilization is encountered with vitamins.

Autoclave conditions inhibit the production of many vitamins such as thiamin, riboflavin, and aspirin. Too harsh for things like corbic acid. In particular, these vitamins iu] bl even when exposed to autoclave conditions. Furthermore, the effectiveness of this method is Autoclave sterilization is affected by the limits of the body.

Patient deaths have been reported, and in many cases it has been difficult to achieve sterilization conditions. This is being followed up.

This is especially true for solution packaging currently on the market. it is, Includes a stopper and a metal cap for securing the stopper to the solution container.

For bacteria under the metal cap, which is designed to keep the stopper free of contamination Achieving lethal sterilization conditions is easy.

It is a good idea to sterilize the stopper by infiltrating the area around the metal cap with sufficient moisture at high temperature. Ru.

The use of autoclaves as a means of sterilization (another persistent problem is The method consists in using a plastic container of some kind for storing the solution.

In that case, the autoclave conditions may result in chemical drying between the plastic components and the liquid contents. May cause interference.

The method of the invention avoids many of the problems associated with autoclave sterilization. parable For example, many patients need amino acids, monosaccharides, lipids, vitamins, fat B minerals, and trace minerals. Requires a complex solution containing neral to be administered intravenously. The current situation mentioned above Because of this technology, these nutritional supplements can be placed in multiple containers and used for patients. It must be.

For example, one common method is to use a bottle of amino acid solution, a bottle of glucose, a large number of Prepare a bottle of vitamins and minerals, either individually or mixed.

Next, the hospital pharmacist or intraluminal solution technician administers these nutritional supplements under sterile conditions. be responsible for adding to the

This process is laborious and potentially dangerous.

Also, it is almost impossible to obtain an accurate concentration of the resulting solution. Because many This is because it is difficult to calculate the final solution volume after adding nutrient substances. Ru. According to our invention, drugs and nutrients that were previously unstable, incompatible, and The drug is conveniently delivered under sterile, pyrogen-free conditions for final administration to the patient. Packaged in a single container.

Dry packaged products made by the method of our invention (4. Parenteral use in nutritional therapy) Greatly expands the flexible use of solutions. Our inventive method can handle both simple and complex static It allows intravenous solutions to be delivered safely and economically to the patient's bed.

Summary of the invention The present invention provides a method for intravenous administration to mammals including humans. A method of making a stable, dry-packaged, sterile, pyrogen-free nutritional composition. hand, A solid nutritional supplement having a moisture content of not more than about 30% by weight of the solid, 11 components. However, if the nutritional supplement is made of amino acids or carbohydrates, the water content should be prepared. does not exceed about 15% by weight, and if the nutritional supplement is a vitamin, the water content I should be about 1 0% by weight, this solid is readily soluble in water at temperatures below about 185°C to form an aqueous A solution is formed, which is filtered through a 5 micron filter at a rate of at least 1 ton per hour. Passes by gravity and the F liquid is 0.22 microns at a rate of at least 1 ton per 2 hours. passing through a lon filter by gravity; Containing and administering the prepared nutritional composition in a sterile, pyrogen-free liquid moisture-impermeable, microbial-impermeable, ionizing radiation-transparent containers adapted to Sealed in: and this sealed composition is subjected to non-destructive, sterilizing ionizing radiation a method comprising exposing the patient to a dose that causes the

The method of the invention provides a nutritional composition in dry packaged form. This is a note to people Sterile, suitable for parenteral use to obtain a nutrient solution composition acceptable for administration. pyrogen-free water.

This composition is a completely sterile, pyrogen-free solution with particulate matter within acceptable limits. and nutritional supplements and 7 Special Table 1987-501226 (4) The sterilization process contains molecules that are not degraded or degraded.

The present invention also provides storage-stable, dry-packaged products and products made by the method of the present invention. including methods of using it to administer nutrients intravenously to mammals, including humans. .

As used in this specification and claims, the words "slow-free" and "sterilize" , Council on Pharmacy and Chemistry of Established by the American Medical Association United States for liquid compositions that do not follow the classical definition and can be administered intravenously Within the limits described by Pharmacopia'X [X (page 592)] Refers to the absence (or killing) of undesirable microorganisms.

As used herein, the term "pyrogen-free" refers to the detection of pyrogens, gave a negative reaction in the well-known horseshoe crab test and means a substance that satisfies the requirements of the intellectual rabbit test as described in IA (see above). Ru.

The term "ionizing radiation" as used in this specification and claim 1 refers to ionizing radiation. It means shooting. The term ``ionizing radiation'' refers to radiation that creates ions or breaks chemical bonds. means radiation with at least sufficient energy to destroy Radiation such as ``quadrupole radiation'' and radiation called ``ionizing electromagnetic radiation'' Also included.

The term "ionizing particle radiation"1 refers to electrons or tsl altitudes ((accelerated relatively Heavy nuclear particles such as protons, neutrons, alpha particles, deuterons, beta particles, or particles are irradiated. used to refer to the radiation of a similar substance that is made to penetrate into an object.

Charged particles are generated by Vander Graff, an accelerator with a resonance chamber. raw equipment, insulated core transformers, betatrons, synchrotrons, cyclotrons It can be accelerated with the aid of voltage radiants by devices such as rotrons and the like.

Neutron radiation bombards selected light metals, such as beryllium, with energetic positive particles. It can be created by converting. Particle radiation is also used in nuclear reactors, radioactive isotopes or by the use of other natural or artificial radioactive substances.

``Ionizing electromagnetic radiation Jid, a metal target such as tungsten is a suitable Created when bombarded with energy electrons.

This energy is a potential accelerator of more than 10,000 engineering Lectron volts. is given to the electron by

In addition to this type of radiation, ions, commonly referred to as X-rays, are suitable for the practice of the present invention. electromagnetic radiation emitted by nuclear reactors or by natural or man-made radioactive materials such as cobalt. 60.

The use of cobalt-600 as a source of ionizing radiation to produce gamma rays 1d in the method of the invention It is preferable.

The word ``nutrient'' (rl, commonly used to mean a substance that gives nutrition, 2 a substance that gives nutrients) It is used in the sense of being able to stay. It includes sugars, minerals, vitamins, amino acids, and proteins. Hydrolyzed natural products, oligopeptides, keto and hydroxy analogs of amino acids, starches and For gelatin and plasma expansion (including analogs used).

The word "medicine" i, -11, in its commonly used meaning, such as meaning a therapeutic agent. It is used in antibiotics, anticoagulants, antiarrhythmic agents, and cancer chemotherapy agents, etc. includes.

Brief description of the drawing FIG. 1 shows a packaged nutritional composition made by the method of the invention and intravenous administration to a mammal. FIG. 2 is a plan view of the means for internal administration.

FIG. 2 is an isometric portion of a packaged nutritional form of another embodiment of the present invention.

Is Figure 3 on line 3-3 in Figure 2? FIG.

FIG. 4 is a partial view of the package seen in FIG. 5, but not folded.

Detailed description of preferred embodiments of the invention The nutritional composition prepared by the method of the present invention contains amino acids, dextrose, and electrolytes. minerals, vitamins, mixtures thereof and similar nutritional compositions. It will be done. In the method of the present invention, they first allow parenteral administration to humans. Prepared in solid form with purity (other than sterility).

Of course, they can be prepared under sterile conditions to allow parenteral administration. carefully prepared can be done, but this is unnecessary.

It is recommended to first prepare a nutritional composition with a water content of about 0.2%. Essential to the method of invention. In the absence of this minimal moisture, it is sterile. I don't know if sex will not be achieved satisfactorily. In other words, the nutritional composition l' It may be affected or deteriorated.

A maximum moisture level also exists. Above this it varies depending on the desired nutrient composition. Will. Generally, the maximum allowable moisture content is 74%, about 50% by weight of the nutritional composition. It is. However, if the nutritional supplement is amino acids or carbohydrates, the water content will be approximately 15%. % by weight, preferably in the range of about 4-8% by weight of the composition. No.

If the nutritional supplement is a vitamin, the water content should not exceed about 10% by weight of the composition. However, it is preferably 3% or less. If the nutrient is a mineral, the maximum ~ water content must not exceed 30% by weight.

The moisture content is preferably 20% or less.

If these water contents are exceeded, the nutrients will lose 50% of water during sterilization. , It might be worse if you hit it.

■ For use, the "consumed nutritional supplement" composition does not contain pyrogens. This thing I also Immediately after preparation of the nutritive composition, it is added to the water content described above by the process of the present invention. would be warranted if maintained until sterilized in a vacuum.

For parenteral administration, the purity of the nutritional composition used with respect to particulate matter contamination is important. Those skilled in the art will appreciate that it is important to meet certain criteria. we We have found that the products of this method will meet these requirements and criteria.

Preferably, the initially prepared nutrient composition satisfies the following particulate matter test:

The manufacturing loft of dry, solid form nutritional compositions is first carried out in a dry, clean container. I get rolled over. Take out a randomly selected part and add 1 ton of warm water (185”F) and pass by gravity through a 5 micron filter. This 1t service The sample must pass through the filter within 1 hour. If the sample If this test is not passed, the starting nutritional composition is treated with the method of the invention. undesirable for

2 1 t of solution, if it passes the first filter test, then Gravity passes through a 22 micron filter.

If the MoLJ' liquid passes through a 0.22 micron filter within 2 hours, then this Is it preferable for the starting nutritional composition to be further processed in the method of the invention? It shows. This nutritional substance 1 prepared in the first step of the treatment by the uninvented method is , and must also pass the USP XIX test for nonpyrogenicity.

Preferably, the nutritional composition initially provided has as little bioload as possible. Two.

ie it preferably has low bacterial contamination. in the most preferred form If the nutrient composition is initially prepared, it is tested for the presence of bacteria. When the medium count is less than 10 per 1f or 1 colony per 1f is shown. must be bacteria-free. If bacterial contamination occurs in this nutrient composition, If the pot is kept at low temperature from the time of manufacture of the product until it is processed by the method of the present invention, Heat source view (Ha, probably a low level.

The initially prepared nutritional composition is then made into a moisture-impermeable, microbial-impermeable material. Receive and administer sterile, pyrogen-free liquids that are transparent to ionizing radiation. hermetically sealed in a container suitable for Preferably, the nutritional composition is prepared over a period of several years. Non-metallic materials that will effectively exclude the ingress of microorganisms, gases, vapors and moisture over time Sachets and multi-layered containers made from substances, such as overlapping! d”11J:1. sealed in a container. Such packaging materials may contain two or more layers of film. Polymer films are available commercially in various forms, including laminates.

Parable bags are made of polyethylene, polypropylene, polyethylene terephthalate. , polyvinyl chloride and similar polymers for making hermetically sealed sachets. - can be composed of film. This container is initially placed in clean, particulate-free conditions. must be prepared using conventional techniques such as ultraviolet irradiation. It will be appreciated that pre-sterilization can be carried out to some extent using .

After the nutritional composition has been sealed in the above-mentioned container, it is previously prepared according to the method of the present invention. A non-destructive (non-degrading), sterilizing dose of ionizing radiation as defined. be forced to

We use ionizing radiation, non-degrading, and sterilizing sealed nutritional compositions. It is found that the dose to which preferably does not exceed 4.0 megarads.

Radiation within this dose range may be administered at room temperature or, if desired, below or at elevated temperatures. temperature.

The temperature at which the radiation takes place is not critical for the method of the invention.

However, practical temperatures are within the range of about -10 to +50°C. Lower radiation dose/ Well, it's not very effective at sterilizing sealed nutritional compositions. higher radiation Linemeters generally determine whether the packaging container and/or the nutritional composition contained therein has deteriorated (broken down). Dechiro).

this! is, of course, undesirable.

For this reason, the doses used to sterilize sealed nutritional compositions are Preferably from about 1 to about 5 megarads, most preferably about 2.5 megarads.

However, under conditions of higher radiation doses without deteriorating the packaging or nutritional composition, It is possible to use For example, this can be done by first creating a sealed nutrient composition. Achieved by lowering the temperature to an extremely low temperature, for example to the temperature of liquid nitrogen or its vicinity. It's a little boring. Cooling the nutritional composition and its container to this low temperature prior to irradiation It can also promote sterilization. In addition, if the nutritional composition is exceptionally dry, for example, if it has a water content of less than 1% by weight, radiation up to 6 megarads. The amount will not detectably degrade the nutritional composition.

From the above considerations, the dose of ionizing radiation depends especially on the moisture level of the material being irradiated. It is clear that it is possible to change it to some extent.

The lower the moisture level, the higher the capacity of the radiation meter without deterioration of the nutrient material. It becomes.

The above-mentioned irradiation (d) may also advantageously be carried out in the absence of an oxidizing agent, e.g. sufficient that the baby's body reacts with the nutritional composition and its packaging material during irradiation. It can be carried out in an atmosphere with a significantly reduced gas intensity. The decrease in oxygen present is , by packaging under and in the presence of an inert gas atmosphere, such as nitrogen. Or irradiation in the presence of nitrogen rather than oxygen atmosphere is achieved through the use of partial vacuum packaging. , the six-pronged prong 1 reduces the secondary prong 1 indirect destructive action of free radicals that occur in the presence of oxygen. Let it go down.

There is only one direct effect of direct bombardment with ionizing radiation.

As mentioned above, gamma radiation made of cobalt-60 can be used in the method of the invention. Chill with a preferable ionizing radiation. The gamma radiation produced by cobalt-60 is It has high penetration power and eliminates the need to worry about the thickness of the nutrient composition being penetrated.

The fact that microorganisms exposed to radiation, including gamma radiation, do not always die immediately is that well known.

Some species of bacteria are exposed to radiation doses that prevent their growth. Many biological functions continue for long periods of time. For this reason, for the method of the invention Sterility testing performed as a control measure should be delayed until 4 days after radiation. No.

Equipment for producing ionizing radiation and applying it to various substances, including food, for example. Since the techniques for doing so are well known, there is no need to explain them further here.Those skilled in the art will be well versed in the technology of adapting to ionizing radiation.

Now, it is a plan view of a dry packaged nutritional composition made according to the method of the present invention. A greater appreciation of the preferred embodiment of the invention will be gained from FIG.

As seen in FIG. 1, a dry packaging device 0 is illustrated. This is the nutritional composition A sealed container of polymeric film containing a substance such as dextrose powder 14. It consists of 12 bags.

The sachet 12 also has a 10 ml droplet between the dextrose powder 14 and the outlet tube 16 at one end. Includes a particulate screen 18. The inlet pipe 20 is connected to the reduced pressure condition when the ball valve 22 is opened. hermetically sealed under conditions and irradiated with gamma radiation according to the method of the invention described above.

When the nutritional composition is desired to be administered intravenously to a patient in need of nutritional treatment, Sterile, pyrogen-free water can be provided in a sterile container that can be connected to a source of water. Via the nectar 24 it is introduced through the tube 20 leading to the pulp 22. sterile pyrogen-free water is introduced into the sachet 12 at the ball valve 2. 2 is squeezed and 14 dextrose is added by squeezing the sachet 12 or It can be dissolved in one go.

In order to provide an indication of the water introduced into the pouch 12, as shown in FIG. A scale may be printed on the surface of the pouch 120. Administer dissolved dextrose powder 14 to the patient. The sachet 12 is suspended in the gap 26 and the rotating clamp 28 is opened and the solution passes from inside the pouch 12 through the screen 18 and into the tube 16. It can be made to flow smoothly.

The tube 16 includes a drip chamber 30 and an additional in-line filter, such as a 0.22 mic filter. A Ron filter 32 is attached to the open end of the middle tube 16 and the mammal @ animal is kept at rest. A needle 36 is inserted into the vein, and the dextrose solution is controlled by a clamp 28. It is administered into the body while being treated. Additional means in the form of an inlet 68 are provided for injecting drug and dissolving. Provision may be made for mixing the dissolved dextrose powder 14. Advantages of the present invention In a preferred packaging, the pre-assembled tube 16, adapter/needle 36 and the above-mentioned The entire sachet 12 with other components such as It is prepared in an outer packaging. At this time, all parts are ionized as described above. Sterilized by radiation.

For use, the operator must open the outer non-traditional packaging and remove the Remove the sachet 12 and use aseptic technique to fill the interior of the sachet 12 with a sterile, pyrogen-free material. Add water to make a solution of dextrose powder 14 and insert it into the patient's vein with the needle 36. Prepare and administer the entire dissolved nutrient solution using aseptic technique and conventional procedures. It is necessary to

From the foregoing, it is important to note that storage-stable, dry-packaged topical compositions may be shipped far from the manufacturing facility. It will be understood that it can be prepared at any point or location.

Immediately before use, water for parenteral use is added to make the final solution. Portable equipment Can be used to make sterile, pyrogen-free water for the preparation of the final solution; See, eg, US Pat. No. 4,089,749.

In relation to Figure 1, for illustrative purposes? C science nutritional composition dextrose 1 sachet I explained that I could put it in 2. For administration to mammals suffering from nutritional deficiencies. It will be appreciated that it may be desirable to make nutritional composition mixtures for .

Generally, different types of nutritional compositions are separated from each other until dissolved in an aqueous medium. For example, as mentioned above, it is desirable to combine amino acids and dextrose. Mylar after mixing for a considerable amount of time, even at moderate moisture levels and room temperature. reaction occurs.

This ultimately shortens the shelf life of the packaged nutritional mix composition.

In addition, from the above study, it was found that the type of nutrient composition consisting of It will be appreciated that the total water content must be maintained at a different level.

For example, minerals are generally very hygroscopic and dusty, with normal humidity such as 20-30% humidity. absorbs water under environmental conditions.

Some salts are also hydrating, which means they tend to bring water inside a sealed container. There is a direction. Preferably such minerals are minerals such as amino acids, which are normally drier. Separated from acid and/or dextrose material. This 1d single unit It is used for packaging a large number of dry nutritional compositions in a container, and is used for preparing solutions. storage stable until it is desired to administer the solution to a person in need of such treatment. Dechiru.

As illustrated in FIG. Consists of a sachet of film.

However, the pouch 50 is folded once in its center, forming a fold line 52. and is fastened by a 'U' shaped member.

This effectively turns the interior space formed by pouch 50 into two separate chambers. sachet For details of the structure of 50, see Figure 3, which is a cross-sectional view taken along line 5-3 in Figure 2. It is clearer with j.

That is, the fold ensures that the pouch 50 has two internal chambers 56, 58. , this fold is clamped by a demarcating clamp member 54.

Referring now to FIG. 4, this shows a view of most of the pouch 506 shown in FIG. However, However, the clamp member 54 has been removed, and the pouch 50 is in the expanded state 1.

In this state, the chambers 56 and '58 are in communication with each other.

As shown in FIG. 4, walls 60 and 61 are sealed by heat sealing the sides of the pouch. Formed within the chamber 56, independent sub-chambers 62, 64 and 66 are formed within the chamber 56. It will be done.

Minerals, amino acids, drugs and/or vitamins are contained in relatively small chambers 62, 64 and 66. tamins and can be separated from each other in chamber 56. Next, inside room 58 ,parable? You can also add carbohydrates like dextrose.

Under these conditions, a single sachet of 50 contains minerals, amino acids, vitamins and carbohydrates. and keep them mutually compatible before they are desired to be mixed into an aqueous solution. It will be easy to see that the scales used to separate the components are all effective.

In other respects, the pouch 50 is similar to the packaging device 0 of the embodiment shown in FIG. tube 16 with filter 32, inlet 34.7 adapter/needle 36, clamp 28, tube 20, pulp 22 and sterile connection 24 are all attached. Ru. All of these (not all shown in FIG. 4) are described with respect to packaging device 0. It works the same as explained.

In operation, the Id1 clamping member 54 is removed and described in relation to the packaging device 0. Only use sterile, pyrogen-free, particulate-free water.

Administration to humans is also the same as described for packaging device 0.

The following examples describe ways and procedures for making and using the invention, and provide instructions to the inventors for making and using the invention. A mode of carrying out the present invention that is considered to be the best is described, but is interpreted in a limited manner. Shouldn't. In performing the practical example, the following tests (if listed) are used: Pyrogens - Representative samples were tested for the chemical detection of pyrogens. It was put on strike. If horseshoe crabs are positive for pyrogens, remove that lot. It will be done. If the sample is not positive or slightly positive for pyrogens, That sample! Rabbits as outlined in the Four Congregations of Pharmacopia, XIX further tested by test. If the temperature in each of the three rabbits is This sample is acceptable if the temperature rise is zero or less than 1°C; transferred to processing. If the sum of the temperatures of the three rabbits is higher than 3℃, then this robot The cut is excluded.

Sterility - If the representative sample/pull is irradiated material, for total pond count Tested using standard methods. Samples found negative are then subjected to sterile Follow the technique recommended by Pharmacopia XIX in the United States of America. Serially diluted on culture slants.

Amino acid status, storage control (pure sample) and treated (irradiated) sample sample using a standard liquid chromatography amino acid analyzer.

Preservation of dextrose - dextrose (pure sample) and processed ( irradiated) samples by optical rotation for overall differences and Lyle ester derivatives were tested for degradation products by gas-liquid chromatography. Inspect.

Example 1 A flexible polyvinyl chloride sachet type container with a 500-kg container was selected. Ru.

It is cleaned of particulate matter by washing and blowing with clean air. number 1 solid sachet with a moisture content of 8% (Karl Fischer method) and 10/l Each is loaded with anhydrous dextrose powder 252 with a low bacterial count.

This dextrose powder is made by mixing 250 tons of dextrose in warm water (185”F) for 10 minutes. 00- and pass the solution through a 5 micron granule filter in less than 1 hour. Filter the filtrate through a 0.22 micron air and bacteria filter by gravity. Particulate matter is removed from the manufacturing loft tested by passing it in less than 2 hours. selected.

As stated above, this loft has been tested for pyrogens and found to be pyrogen-free. Ru.

A container containing anhydrous dextrose powder is purged with nitrogen gas and reduced. Sealed under pressure.

The filled container is then exposed to a cobalt-60 source until it receives various radiation charges. be forced to

After 4 days, fill the sealed, irradiated package with 500ml of sterile, pyrogen-free water. Make a 5% dextrose aqueous solution.

A portion of the solution was tested for sterility, particulate matter, deterioration of nutritional composition and pyrogens. will be attached to the The radiation sources used and the test results are shown in Table 1 below.

Table 1 9 0.62 - 99.7 74 10 1.25 - 100.6 9611 2.50 - 99.6 97 14 2.50 match - 5 Control: None 99.9 99 16 possible Control: No pyrogen Packaging devices 2.14 and 16 are tested for the presence of particulate matter as described above and It was found that it did not contain any substances.

Example 2 Repeat the procedure of Example 1 above. However, dextrose powder contains 0.4% water. Sow the amount. The test results are shown in Table 2 below.

Table 2 352.50 -- 100 38 2.50 Match - 0 No control Example 3 Freeze the procedure of Example 1 above. However, the anhydrous dextrose used there , replaced by the following mineral mixture: Mineral millimeters Sodium chloride 45 Potassium acetate 25 Potassium superphosphate 12 Magnesium sulfate 2 Calcium gluconate 1 Zinc sulfate 5 Sulfur @ 1 The mineral mixture has a water content of 15.8%. Implement mineral composition 152 Seal in a sachet container as described in Example 1 and irradiate.

Irradiance levels and test results are shown in Table 6 below.

41 0.62 Match 42 1.25 p 43 2.50 tt 44 0.62 rt 45 1.25 46 2, 50 p 48 (爛) Nashi No Example 4 The procedure of Example 1 described above is repeated 4 times. However, the anhydrous dextrose used there , replaced by a vitamin mixture 2.52 of the following composition: Vitamin percentage Ascorbic acid 500■ Thiamin hydrochloride 25 ■ Riboflavin 5 ■ Pyridoxine Hydrochloride 7.51η Nicotinamide 50 miles It has a moisture content of less than 20%. Tested to be sterile and pyrogen-free. A vitamin solution is obtained which shows that

Example 5 Repeat the drying procedure of Example 1 above. However, the anhydrous dextrose used there is replaced by the amino acid mixture 42.59 below. Amino acid section L-isoleucine 5.9 L-phenylalanine 4,8 It has a water content of 19%.

An intravenous solution of amino acids is obtained. The test results are shown in Table 4 below.

7 (tears) 0 No deterioration 8 (control) 0 no - Packages 4, 6 and 8 have been tested for particulate matter and must be free of such material. It turns out.

Those skilled in the art will appreciate the preferred embodiments described above without departing from the spirit and scope of this discussion. You will probably agree with the scales with many modifications.

For example, drugs and similar medications may be packaged in nutritional compositions made by the method of the present invention. can be included, mixed with it if compatible, or separated until use. If desired, it is isolated in a separate pouch of the container of FIG. the Representative examples of such drugs include antibiotics and antifungal substances.

Submission of Translation of Written Amendment (Article 184-7, Paragraph 1 of the Patent Law) June Sθ, 1988 Mr. Kazuo Wakasugi, Commissioner of the Patent Office 1. Display of patent application PCT/US 81101061 , Title of the invention Method for preparing and using intravenous nutritional composition 6 patent applicants Address (Residence) Newton, Wells, Massachusetts 02159, USA Venue 189 Name: Delmdo Incorporated [Telephone 03 (502) 1476] (Representative)] 5. Date of submission of written amendment December 29, 1981 Amendment to Rule 46 Pages 24, 25 and 26 of the attached replacement for those specified above. d. The scope of claims is amended as follows: Lines 6 to 7 of Section 1 of the Claims Act, between “r not” and r more J Features 1ess than about O, 2and not J In the first line of claim 9, dependency on claim 1 is changed to dependency on claim 8. I can do it.

In the last line of claim 11, at the end of this line and before the period, it is stated that ``sterilization is performed by ions.'' Characterized by ``Achieved by chemical lines'' Characterized by claim 21 Scope of claim! for 1. A stable, dry-packaged, sterile, pyrogen-free product for intravenous administration to the salivary glands. A method for making a nutritional supplement containing 2111 ingredients, Moisture content of solids not less than about 0.2% and not more than about 30% providing a solid nutritional composition having a content; However, if the nutritional supplement is amino acids or carbohydrates, the water content should be approximately 15%. If the nutritional supplement is a vitamin, the water content will not exceed about 1°, and the water content will not exceed the above-mentioned level. Solid 1 is readily dissolved in water at temperatures below about 185 to form an aqueous solution, which passed by gravity through a 5 micron filter at a rate of at least 1 ton per hour; The 775 liquid '40.22 Micron filter at a rate of at least 1 ton per 2 hours If it passes by gravity at a degree; Prepared nutritional composition in sterile, pyrogen-free liquid? contain and administer Moisture-impermeable, microbiologically impermeable, ionically permeable container adapted to When sealed inside; and exposing the sealed nutritional composition to a non-destructive, sterilizing dose of ionizing radiation; and How to include.

2. The claim wherein the nutrient composition is cooled to the temperature of liquid nitrogen prior to the irradiation step. The method described in box 1.

3. The method of claim 1, wherein the nutritional composition includes an amino acid.

4. The method of claim 1, wherein the nutritional composition includes dextrose. .

5. The method of claim 1, wherein the nutritional composition includes vitamins.

6. The method of claim 1, wherein the nutritional composition includes minerals.

B. The method according to claim 1, wherein the container is a pouch formed from a polymer film. .

81. The method of claim 1, wherein said ionizing radiation is a gamma ray.

9. The method of claim 8, wherein the sterilizing dose is in the range of 0.05 to 6.0 megarads. .

10. Claims in which a number of different nutritional compositions are present sealed within the above-mentioned container. Eleventh method.

11. Sterile, pyrogen-free, particulate matter-free Sakae koji Dry packaged for containing the nutritional composition and for intravenous administration to mammals Articles of manufacture adapted to contain compositions in dry form and aqueous mixtures sealed, moisture-tight, microbial-impermeable, ionizing radiation-transparent container : A water-containing acid containing no more than about 30% by weight of the solid material placed in the above-mentioned container. a solid nutritional composition containing an amino acid or a carbohydrate; 'The water content should not exceed 15% gold, and if the nutritional supplement is a vitamin, the water content should not exceed 15%. Minute 1. The solid matter mentioned above is 18! MF; water at a glance Easily dissolved to form an aqueous solution, which requires less than a 5 micron filter per hour. Both pass by gravity at a speed of 1 t, and the filtrate I passes through a 0.22 micron filter. - passing by gravity at a speed of at least 1 t per 2 hours; Intravenous administration of sterile, pyrogen-free water and the nutrient composition in the container described above. connected to a container for introducing into the container in sufficient proportions to form a mixture means; a means connected to the container for administering the intravenous mixture to the mammal; combined with a means for administration adapted to remove particulate matter from intravenous mixtures; One means of filtering; Bacteria-impermeable, hermetically encapsulating the container-supported and connected means. External appearance: Consists of, however, The enclosed containers and means described above are sterile, and the nutritional composition is sterile and pyrogen-free. Articles which are free of contaminants and whose sterilization is achieved by means of ionizing radiation.

12. The article of claim 11, wherein said container has flexible walls.

13. The above-mentioned container is internally divided into a plurality of chambers, and each chamber contains a respective composition of water. In dry form, they are separated from each other except when mixed into a sexual mixture. According to claim 11, the plurality of chambers can communicate with each other. Goods.

14. The article of claim 11, wherein said composition includes an amino acid.

15. The article of claim 11, wherein said composition includes a carbohydrate.

16. The article of claim 11, wherein said composition includes a vitamin.

17. The article of claim 11, wherein said composition includes a mineral.

18. The above-mentioned introduction reservoir means comprises a tube 9, the first end of which is inside the above-mentioned container. with a second end leading to the outside of the container and extending to a source of sterile, pyrogen-free water. and adapted to connect to valve means for opening and closing the above-mentioned pipes. Article according to claim 11.

19. The above-mentioned means for dispensing comprises a tube, the first end of which is inside the container. and a second end leading to the outside of the container, the second end being adapted to be inserted into a vein. The article of claim 11.

20. Claim 1, wherein the above-mentioned filter means is a 022 micron filter. Items listed in Section 1.

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Claims (1)

[Claims] 1. Stable, dry-packed, sewn, sterile, fever's proboscis for intravenous administration into the breasts I think it's a way to make nutritional nutrition that doesn't contain any nutrients. The nutritional value of a solid substance with a moisture content not greater than 30% However, if you prepare the proboscis, the nutritional supplement will not be in the proboscis, which is an amine-carbohydrate proboscis. Is the shape of the eyes ``proboscis'' about 185? It dissolves easily in water to form an aqueous solution at a temperature of It is passed by gravity through a 5 micron filter at a rate of at least 1 ton per hour. and the furnace liquid is passed through a 022 micron filter at a rate of at least 1 ton per 2 hours. to pass by force; Place the prepared fluorophore in a sterile, pyrogen-free container and administer it to the body. A moisture-tight, microbial-impermeable, ionizing radiation-transparent container adapted to sealed in the container; and Exposure of the sealed nutritional composition to non-destructive, sterilizing radiation of ionizing radiation. and How to include. 2. The claim that the nutrient composition is cooled to the temperature of adult nitrogen prior to the irradiation step. The method described in box 1. 111. The method of claim 1, wherein the nutritional composition includes an amino acid. 4. The method of claim 1, wherein the nutritional composition includes dextrose. 5. The method of claim 1, wherein the nutritional composition includes vitamins. 6. The method of claim 11, wherein the nutritional composition includes minerals. B. The method according to claim 1, wherein the container is a pouch formed from a polymer film. . 8. The method according to claim 1, wherein the ionization @ is gamma rays. 9. The line number to be sterilized is in the range of 0.5 to 6.0 megarads, as set forth in claim 1. Method. 10. Claimed broom in which a number of different nutritional compositions are present sealed in the above-mentioned container. Method of Section 1. A dry packaged article of manufacture for administration, comprising compositions in dry form and aqueous mixtures. Sealed, moisture-tight, microbial-impermeable, adapted to contain compounds a container transparent to ionizing radiation; approximately 30 kg of solid material placed in the container described above; A solid nutritional composition having a water content not greater than % In the case of acids or carbohydrates, the water content does not exceed about 15% by weight and the nutritional supplement is In the case of solids, the moisture content is less than about 10%, and the solids mentioned above are less than 185%. It is easily dissolved in water to form an aqueous liquid at a temperature of The gold passes by gravity at a rate of at least 1 ton per hour and the filtrate is passing by gravity through a Chron filter at a rate of at least 1 ton per -2 hours; ; Intravenous administration of sterile, pyrogen-free water and the nutrient composition in the container described above. a container connected to the container for introducing the mixture into the container in sufficient proportion to form a mixture; means; a means connected to the container for administering the intravenous mixture to the mammal; combined with a means for administration adapted to remove particulate matter from intravenous mixtures; One means of filtering: and Bacteria-impermeable, hermetically enclosing the container and connected and connected means The outer covering of: consists of, provided that The enclosed containers and means described above are sterile, and the nutritional composition is sterile and pyrogen-free. Goods that are not included. 12. The article of claim 11, wherein said container has flexible walls. 13. The container described above is internally divided into a plurality of chambers9, each chamber containing a respective composition, In dry form, they must be kept separate from each other, except when mixed into an aqueous mixture. According to claim 11, the plurality of chambers are adapted to communicate with each other. Goods. 14. The article of claim 11, wherein said composition includes an amino acid. Articles of Section 11. 16. The article of claim 11, wherein said composition includes a vitamin. 17. The article of claim 11, wherein said composition includes a mineral. 18. The above-mentioned introduction reservoir means comprises a tube, the first end of which extends into the above-mentioned container. with a second end leading to the outside of the container and extending to a source of sterile, pyrogen-free water. and adapted to connect to valve means for opening and closing the above-mentioned pipes. Article according to claim 11. 19. The above-mentioned means for dispensing comprises a tube, the first end of which is inside the container. and a second end leading to the outside of the container, the second end being adapted for insertion into a vein. The article of claim 11. 20. Claim No. 2, wherein the above-mentioned filter means is an O.22 micron filter. Articles under Section 11. 21. Sterilization is achieved by irradiation of the article with ionizing radiation3. Articles according to Claim No. 11.