EP3223832A1

EP3223832A1 - Method for producing eye drops

Info

Publication number: EP3223832A1
Application number: EP16711274.7A
Authority: EP
Inventors: Marc SCHROTT; Andrea JOCHHEIM-RICHTER
Original assignee: Herr Marc Schrott Central - Apotheke
Current assignee: Herr Marc Schrott Central - Apotheke
Priority date: 2015-03-24
Filing date: 2016-03-22
Publication date: 2017-10-04
Also published as: DE102015205293A1; EP3081220A1; US20180050064A1; WO2016150932A1; US10300088B2

Abstract

The invention relates to a method for producing eye drops, the thus obtained eye drops and to a kit which comprises the eye drops.

Description

Process for the preparation of eye drops

The present invention relates to a method of producing eye drops, the eye drops thus obtained, and a kit comprising the eye drops.

The dry eye is one of the most common diseases in the field of ophthalmology, with the prevalence increasing with age. The dry eye is a multifactorial, as defined by the Dry Eye Workshop Study Group (DEWS Steering Committee)

Disturbance of tear film and ocular surface, which is accompanied by physical-psychological discomfort or visual impairment. Inflammatory processes and hyperosmolar tear film are important factors associated with this condition.

Among the symptoms of the dry eye is often one

Keratoconjunctivitis sicca understood. Keratoconjunctivitis sicca refers to an ocular surface disorder associated with typical symptoms such as foreign body sensation, photosensitivity, itching, burning pain and pressure sensation. In addition, vision loss, reddened eyes, epiphora (drenching), and dry eye sensation are often observed. With reduced tear production, the symptoms preferably occur in the morning. Lies the problem of increased tear fluid evaporation is more frequently mourned in the evening.

For the treatment of the dry eye today a variety of artificial tear substitutes in the form of eye drops,

Eye gel or eye spray offered. For example, the replacement or supplementation of the aqueous phase of the tear fluid by aqueous solutions of thickening agents, such as, for example, povidone, hyproxymellose or carboxymethylcellulose, salts and optionally other active substances, such as hyaluronic acid or lipids, may be mentioned here. Also known is the addition of the superficial

Lipid layer of the tear film through a liposomal eye spray, which reduces the evaporation of the natural tear fluid and prevents premature drainage as a tear over the lid margin. Also known is the sentence of the tear film and the

Reduction of shear forces between ocular surface and song during song movements through fatty ointments. These ointments are, in particular, oil in water emulsions.

The disadvantage of these known products is that they have a relatively short residence time on the cornea. As a result, the appropriate treatment must be applied at regular intervals, which is often uncomfortable for the patient and impossible in some situations. For example, if your eye is markedly dry, drop 1 drop of an aqueous phase into each eye every 30 to 60 minutes for any deficiencies

compensate. For gel-like treatment agents, this disadvantage is at least partially avoided. However, it proves difficult here to provide the cornea with sufficient oxygen. In addition, as with ointments, for a few seconds to minutes, visibility is impaired. Include the corresponding funds

Preservatives, these can be allergic to one

Reactions lead. In case of prolonged frequent use, this can also lead to a worsening of the symptoms of the dry eye.

Also known is the use of punctum plaques. During the discharge of the lacrimal fluid from the lacrimal glands to the nose, the lacrimal fluid is first spread over the cornea via the loft, in order to keep it moist. It is then removed from the conjunctival sac via the tear points (puncta lacrimalia). Punctum plaques are inserted into one or both puncta lacrimalia so that this outflow is reduced. Depending on the model, the plaques may remain permanently in the puncta lacrimalia or dissolve after a few weeks. The main disadvantage of this

Procedure is that by retaining the tear fluid at the same time the inflammatory substances in the

Tears, which changed the dry eye one

Composition, longer stay on the eye. The plaque-induced drainage of tear fluid through the draining lacrimal ducts may also promote infection by bacteria that may emerge from the nasal cavity.

Particularly in the case of pronounced ocular surface disorders, it has been found that the known artificial tear substitutes or the use of punctum plaques do not always lead to the desired success. The artificial tear substitutes contain only a few Ingredients of natural tears. A sustainable therapy is difficult here.

A relatively new approach in the treatment of diseases of the

Ocular surface is the use of eye drops from serum,

especially from self-serum. The advantage of this is that corresponding eye drops have a biomechanical and biochemical similarity to tear fluid. Therapy successes are better here than with otherwise commonly used artificial tear substitutes, as described by E.M. Herold ("Treatment of keratoconjunctivitis Sicca with

Autologous Serum Eye Drops ", Inaugural Dissertation University of Erlangen Nuremberg, December 20, 2012) Autologous serum means autologous serum obtained from the blood of the person who later uses the eye drops prepared therefrom.

One possible method of producing self-serum dew drops is described, for example, by Herold (supra). Here are taken from the patient 100 ml of autologous blood. The blood picture is checked before and after the removal. After centrifugation, the supernatant is sterile pipetted and placed in sterile dropper bottles. Immediately thereafter, the dropper-bottles are frozen at -18 ° C or lower.

Thawed bottles should be stored at + 2 ° C to + 6 ° C for a maximum of one week.

The high proportion of proteins in the serum causes a microbial

Susceptibility. The use of stabilizers or preservatives, however, as well as a pasteurization is not possible

or not desired. By renouncing

Preservatives or antibiotics in appropriate Self-dehumidifying drops pose the potential danger of

bacterial contamination, which in particular at longer

Use of eye drops from the same dosing vessel

or administration container. In addition, the treatment of keratoconjunctivitis sicca is usually scheduled for a period of 6 months or longer. However, withdrawal of 100 ml of autologous blood, as known from the prior art, is not sufficient to carry out the treatment over a longer period of time. Since the blood sample is usually perceived as unpleasant by the person concerned, there is also a need for a production method which contributes to greater compliance and thus to the success of the corresponding treatment. In addition, the other disadvantages of the prior art should be avoided as possible.

Surprisingly, it has been found that the object on which the present invention is based is solved by a process for the production of ready-to-use eye drops, in particular for the treatment of the dry eye, which comprises the following steps:

a) collection of whole blood at a first location and subsequent b) separation of the blood to obtain serum,

c) Examination of the serum for the presence of pathogens followed by

d) filling the serum into at least one delivery means at a second location,

where first place and second place are different from each other. Preferably, the method further comprises step e) Final examinations before the release of eye drops as a drug for sterility.

If necessary, identity and / or purity can also be checked during the final examination.

Ready-to-use eye drops for the purposes of the present invention are those eye drops that can be used directly by people. The delivery of serum eye drops is a

Pharmacy-bound operation. The filling of the serum into an administering agent takes place in the method according to the invention in the pharmacy. The blood collection itself takes place at another location. This is for example with a device as described in WO

2010/136535 AI is described, not possible because of

Blood collection bag is directly connected to the administration means. Carrying out the blood collection in one place, for example the blood donation service, and the filling of the serum in a second one, according to the legal prescription in a pharmacy, make it possible to deliver the eye drops in a pharmacy, for example near the place of residence or near the place of residence

Workplace of the user.

The removal of larger amounts of blood than 100 ml or more than 200 ml, for example of 500 ml, is preferably carried out as part of a whole blood donation. By blood or whole blood is meant the blood, which contains all native components. The

Whole blood donation can by standard procedures of one

Transfusionmediziener for example in appropriate

Blood donation centers are removed. A whole blood donation, at the about 500 ml of blood can be withdrawn after its

Separating the receipt of about 230 ml of serum. From this serum can then be obtained eye drops that provide a care of a person suffering from dry eyes, over a period of up to half a year. The method according to the invention thus makes possible a long-term treatment without the need for further blood collection, which results in improved compliance and thus also better treatment success.

The withdrawal of 500 ml of blood corresponds to the amount of blood that is usually taken during a whole blood donation. The removal of more than 500 ml of blood and the further processing to eye drops from self-serum is possible in principle. Out

From a medical point of view, however, it is recommended to limit a blood donation to 500 ml. This removal amount is harmless to the human organism. According to the invention, it is also possible to remove less than 500 ml of blood, such as, for example, 300 ml, 350 ml, 400 ml or 450 ml. Again, a longer-term care of people with serum eye drops is still possible. However, the removal of less than 200 ml of blood is not recommended, as more frequent blood sampling is necessary here, making the

Compliance and thus the treatment success are reduced.

According to the invention, the whole blood may be autologous or allogeneic whole blood. Autologous whole blood means that the eye drops taken from the serum are used exclusively by the person who has also donated the blood. In the case of allogeneic whole blood, blood donors and users of the eye drops are different persons. The use of autologous whole blood has the advantage that only

endogenous substances are present in the Eigenserumaugentropfen then obtained. Are people, for example, on reason

If you are unable to donate blood yourself, an allogeneic donation will still allow you to donate blood

Providing these persons with serum eye drops. Allogeneic whole blood thus allows a treatment which would not be possible with autologous whole blood, since this is not available.

Due to the multiple possibilities for testing the whole blood as well as the serum in the process according to the invention, the

Compliance of serum eye drops from allogeneic whole blood can be improved and the safety of the product can be increased in the sense of absence of contaminants.

The separation of the blood into its blood components is carried out by coagulation. This is preferably done over a period of 15 minutes to 70 minutes at room temperature. Room temperature for the purposes of the present invention is a temperature in the range of 15 ° C to 30 ° C, in particular from 18 ° C to 25 ° C. Coagulation is the coagulation of blood. This leads to a separation of the blood components. After coagulation it is

According to the invention possible to store the blood at + 2 ° C to + 8 ° C. Storage may be overnight, for example, but should not exceed 48 hours due to the microbial susceptibility of the serum. In addition, an enzymatic degradation of the blood components begins after about 48 hours. On the other hand, one is Storage of 12 to 48 hours preferred because it can be ensured that the coagulation is complete.

Following coagulation, if appropriate after intermediate storage, preferably centrifugation of the blood, which has already been at least partially separated by coagulation, takes place. The centrifugation is preferably carried out over a period of 5 to 20 minutes, in particular from 5 to 15 minutes, at 1000 to 3500 revolutions / min, in particular at 1000 to 3000 revolutions / min. At room temperature, the transfer of the thus obtained cell-free serum from the original blood sampling device, for example a blood bag, into a serum suitable

Container. This is preferably an empty blood bag (empty bag, serum bag), which can be welded to the blood bag containing the separated blood via a connecting tube. As a result, contamination of the serum by external influences can be almost avoided.

Separation of the blood, which preferably takes place by means of coagulation and centrifugation, thus gives serum. The physiological serum osmolarity (isotonia) in humans is usually 281 to 297 mosmol / l. This value corresponds to that of tear fluid, which results in the preferred use of self-serum eye drops in the treatment of ocular diseases and in particular of

Dry eye results. Furthermore, the pH of both serum and human tears is about 7.4.

The recovered serum is in suitable before filling

Delivery means for the presence of pathogens examined. Within the meaning of the present invention, pathogens are factors which trigger or favor infectious agents or other diseases which may adversely affect the human organism and, especially when used as eye drops, could jeopardize therapeutic success or

could possibly lead to the development of other diseases. Contaminations of the serum may, for example, also occur during the blood collection or the separation of the blood.

In particular, the introduction of germs is improper

Skin disinfection and / or leakage in the blood bag tube system possible.

In addition to the examination of the serum, a corresponding examination of the blood can also take place according to the invention even before the blood sample is taken. This is also recommended because in the presence of contaminants, the blood can be discarded for the preparation of eye drops.

Even if an analysis of the blood was carried out prior to collection, the re-examination of the serum according to the invention provides additional security in order to ensure improved product safety. It is possible according to the invention to store the serum before filling in an administration agent at a temperature of - 20 ° C. In this case, the testing for contaminants preferably takes place after storage and immediately before filling in the administering agent.

According to the invention, the serum is in particular up to the presence of the findings of the infection examination in a temperature-controlled Refrigerator intermediately stored. Are the infection tests negative?

failed, the appropriate batches in appropriate

Dispensing agent be bottled.

When filling the serum in step d) of the method according to the invention, care should be taken that no

Contamination of the serum takes place. Therefore, the filling in step d) is preferably done in a clean room. This can be the

Clean room are located near the place where the whole blood donation is done. However, it is also possible according to the invention for the serum or even the whole blood to be initially moved to another location

is transported and then at this spatially separate other place the workup to the serum and / or the filling in

Administering agent. It should be noted that during transport, the temperature of 10 ° C, in particular of 8 ° C is not exceeded.

Compared to the known from the prior art method, as described for example in WO 2010/136535 AI, there is thus a further advantage according to the invention that the

inventive method allows a location-independent production of Eigenserumaugentropfen, which causes the more flexible application of the method according to the invention. If there is a long way to go for blood collection and preservation of the eye drops for the end user, this also often leads to lower compliance for him. With the method according to the invention, it is now possible that a whole blood donation, for example in a

Transfusion physician takes place. Even if this is for the

Blood donors backtracking distance a certain effort means, this is due to the lower frequency of

expected to be reasonable twice a year. This also supports compliance and thus treatment success.

With the aid of the method according to the invention, it is therefore possible for the delivery of self-serum dew drops to the patient to take place in the vicinity of the place of residence. If the location of the blood collection is several

Kilometers away from the patient's place of residence, then there is the

Burden on the patient only to go there once in 6 months. After the separation of the blood that allows

The inventive method, the transport of the serum, for example, in a pharmacy, which preferably has a clean room. In this pharmacy, the serum can then be filled and delivered in single doses to the patient. Alternatively, it is also possible that the clean room is located near the place where blood is collected. Here can be done after filling in the delivery of the transport to a local pharmacy. The

inventive method thus allows an extremely high flexibility, which leads to a near-residential care of the patient with Eigenserumaugentropfen.

Therefore, the method preferably comprises the following steps:

a) collection of whole blood in a blood bag at a first location, b) separation of the blood to obtain serum at the first location, bl) transfer of the serum under sterile conditions to a serum bag at the first location,

c) examination of the serum for the presence of pathogens in the first place and simultaneous transport of the serum to a second location, d) filling the serum into at least one delivery agent at the second location.

Alternatively and also preferably, the method comprises the following steps:

a) taking whole blood in a blood bag at a first location and then transporting the whole blood to a second location,

b) separation of the blood to obtain serum at the second site, bl) transfer of the serum under sterile conditions into one

Serum bag at the second place,

c) examination of the serum for the presence of pathogens in the second place and

d) filling the serum into at least one delivery agent at the second location.

The filling of the serum in the administering agent can be carried out in a simple manner, for example by means of a three-way stopcock. Of the

Three-way stopcock is thereby connected with a connection to a bag in which the serum is located (serum bag). Corresponding bags usually have a hose to which the

Three-way cock can be connected. To another

Connection of the three-way valve can then be connected to the administering agent. The position of the cock then controls the filling of the serum into the administering agent. Depending on the volume of the serum and the volume of the administering agent, it is possible to connect to the third connection point of the three-way stopcock either another serum bag to a complete

Allow filling of the administering agent. However, this is not preferred, as it leads to cross contamination between the Serum batches can come. Preferably, another administration container is connected to the three-way cock. The

inventive method allows the receipt of a large

Volume of serum. If it is not possible to fill all the serum into one delivery agent, a new delivery agent would need to be attached to the serum bag. By using the three-way stopcock this change can be avoided and the entire volume of serum can be filled into suitable administration agents.

The filling preferably takes place in a clean room. This avoids further infection of the serum. Prefers

Administration means in the context of the present invention

Administration containers.

Suitable administration containers are known in the art. A possible administration container, which is described in DE 20 2011 004 487 Ul, comprises a collecting and

Venting container, which via an end line with the

Administered administration containers, wherein the

Administration containers are each provided with opening means and are connected by flow. The

Delivery containers can be connected by means of a sterile piece of tubing to the serum bag, for example by means of a three-way stopcock. The individual administration containers each have a volume of about 3 ml.

The disadvantage here is that the hose system with which the

Administering containers are interconnected, a volume which collects serum that is not available for use as self-serum dew drops (dead volume). The individual administration containers are also made of one

yielding or soft material. Depending on the applied pressure different amounts of drops are delivered. The

Volumes that are used for the therapy and the duration of treatment can not be predicted. In addition, the large opening carries a high risk of contamination of the bottle contents, for example with bacteria or fungi. Once the disposable doses are opened, they can not be resealed, leaving the ones available in each administration container

Eye drops must be consumed within a few hours or discarded due to the risk of contamination. Due to the large dead volume and as well as the extremely short

Shelf life of each administration container, is the amount of eye drops that is available, compared to the

decreased amount of blood low, so that multiple blood draws are needed to provide patients with a sufficient amount

To provide eye drops over a longer period of time.

Preferably, the administration container is a pumping system which comprises a container for receiving the eye drops and a pumping device for metering the eye drops into the eye. The pumping system is designed so that it is suitable for multiple use. The amount of eye drops contained therein is sufficient, for example, to provide a supply of eye drops over a

Period of one week or longer. Significantly longer application times per vessel are not desired due to the risk of contamination. The amount of serum removed is sufficient to allow a filling of several pumping systems. A pumping system is then delivered to the patient, the others are preferably stored at the second location, ie in particular in the pharmacy, with cooling. If necessary, the eye drops are then delivered to the patient

output. As the pharmacy, so the second place, as possible

Close to home, compliance will not be reduced.

At the same time, however, necessary professional storage of the eye drops takes place over a longer period of time. at

or before each issue of the eye drops is a

Control in the pharmacy, whether the eye drops can still be used and the patient can be informed in good time on the need for a new blood collection, so that a constant supply of eye drops and their control is ensured, without doing so with a great effort for the Patients, so the user of the eye drops, connected, since the second place near the home or in another suitable place, such as in the vicinity of the workplace, can be selected.

Particularly preferred are pumping systems designed such that microbial contamination of the eye drops during use is substantially avoided. This can be done by the design of the pumping device, in which, for example, a membrane may be contained, through which the eye drops can escape to the outside, but pathogens not into the interior of the

Pumping system. Alternatively, the pumping device may also be a

antibacterial device, such as a silver spiral, include. Corresponding pump systems are described, for example, in EP 1 380 351 A1.

In a preferred embodiment, therefore, the method comprises the following steps:

Serum bag at the second place,

d) filling the serum into at least one administration means at the second location, wherein the administration means is a pumping system comprising a container for receiving the eye drops and a container

Pumping device for metering the eye drops into the eye.

According to the invention, the filling of the serum takes place in that preferably removed in a clean room under sterile conditions by means of a sterile syringe serum from the serum bag and the multidose drip system (dosing) is filled with pumping system with 5 ml. The attachments of the dosing bottles are placed manually, a sleeve added to protect against breaking the bottles and sealed by operating a lifting press firmly with the bottle. The filter contained in the dosing bottle or the pumping system protects the serum from microbiological contamination. A silver spiral in the tip prevents that

Growth of germs. This is the dead volume, so the amount of serum that is discarded and not available as eye drops is very low, whereby the number of blood samples can be kept low.

An appropriate pumping system allows a defined

Single dosing in a row from the same container. Compared with other administration containers, the advantage here is that the self-serum eye drops can be stored over a longer period of at least 7 days for the patient in the refrigerator, ie at a temperature of + 2 ° C to + 8 ° C, or even at room temperature without contamination with aerobic or anaerobic bacteria or fungi. By contact with the silver spiral in the dosage of the eye drops they are kept substantially free of microbes. Gelichzeitig is the

Effectiveness of eye drops is not affected.

According to the invention, it is therefore recommended that the serum after filling in suitable administration containers at a temperature of T <-20 ° C is stored. Here is a storage of at least 6 months possible, without causing contamination of the

Eye drops are coming. Will the stored so deep frozen

Thawed drops and stored at a temperature of + 2 ° C to + 8 ° C or stored at room temperature, they are at least 7 days or more durable without contamination and thus used by the patient. Due to the method according to the invention, it is possible to visit the patient weekly with new ones

To supply eye drops. This ensures that storage at -20 ° C in a pharmacy is temperature-controlled. Single doses, which in a household usual refrigerator, thus with a

Temperature of + 4 ° C to + 8 ° C, or at room temperature can be handed over for at least 7 days. Thus, even such persons over a long

Period are supplied with serum eye drops in which a blood sample, for example, due to health problems is not or only rarely possible.

According to the invention, it is possible for the preparation of the eye drops, the serum before or during filling in suitable

Administration containers is diluted. This dilution can be carried out, for example, by means of known artificial tear replacement agents which comprise, for example, isotonic saline solution and / or active substances such as hyaluronic acid and / or lipids. The dilution may be in the range of 10% to 30%. This means for the purposes of the present invention that based on 100 wt .-% of eye drops, these consist of 90 wt .-% of serum and 10 wt .-% of tear substitute. Correspondingly, a dilution of 20% by weight means that the eye drops consist of 80% by weight of serum and 20% by weight of tear substitution, and a dilution of 30% by weight that the eye drops consist of 70% by weight of serum and 30 wt% tear substitutes.

The dilution of the serum eye drops allows a supply of affected persons over a period of approximately one year or depending on the frequency of use also beyond, which also results in improved compliance. In addition, it has surprisingly been found that in the presence of lesions of the cornea, such as occur in a leukemia disease, protein deposits can occur in the eye when undiluted serum eye drops are used become. By a dilution according to the invention such protein deposits can be avoided.

Furthermore, the dilution allows a long supply of

Patients in particular even if these due to a

Illness can not go back to blood. This may, for example, be the case with a leukemia disease in which stem cells have been transplanted for therapy. Affected patients are at risk of developing a "graft versus host desease" due to an immune response to the transplanted stem cells, which is already among those already diagnosed

described corneal lesions can come in the eye. These can also be well treated with serum eye drops. However, regular blood sampling can not be ensured here due to the disease. The inventive method

allows remedy here.

The dilution should not exceed a value of 30%. At a higher dilution, the flow properties of the eye drops change, so that a good adhesion to the eye is no longer present. In addition, the other properties, such as the protein concentration, are influenced in such a way that the positive properties of the Serumaugentropfen opposite

conventional tear substitutes hardly outweigh.

In addition to testing the serum for the presence of disease and / or infection prior to serum filling, it is

According to the invention, it is further preferred that at least once randomly, even after the filling of the serum into administration containers two administration containers are selected and the serum contained therein is re-examined for the presence of diseases and / or infections. Since, according to the invention, a larger amount of blood is taken at the beginning, there is one

sufficient serum to provide the patient with eye drops over a period of at least half a year and on the other hand by a sufficient number of samples to ensure that even when filling in step d) of the method according to the invention no further

Contamination is done.

In a further embodiment, the present invention further relates to eye drops, which after the inventive

Procedures were made. By the eye drops produced according to the invention is a near-home, long-term care

ensured. Due to the unique blood donation as well as an improved safety from infections, due to the possibility to test the serum, this results in an improved compliance and thus increased chances for a successful treatment of dry

Eyes.

According to the invention, the eye drops for the treatment of

Disease of the dry eye. Thus, for example, patients in which dry eyes in addition to the actual disease, such as diabetes or rheumatism, use appropriate eye drops. Furthermore, the eye drops according to the invention are suitable for the treatment of dry

Eyes, which are considered side effects of drugs, such as

For example, hormone preparations, beta-blockers or psychotropic drugs, occur. Also, corneal lesions on the eye as they pass through

Chemotherapeutic agents can be treated with the eye drops of the invention. The eye drops are not only suitable for illness-related dry eyes, but can also be used by people who work a lot on the computer or because of the workplace in particularly dry, cold rooms.

Furthermore, the present invention relates to a kit which the

Eye drops in a suitable administration container includes.

Suitable administration containers are known from the prior art and allow a constant dosage of

Eye drop. An administration container which comprises a pump system which has a container for receiving the eye drops and a pump device for metering the eye drops, is preferred, since here the quantity of eye drops which occurs in the case of the eye drops

Use is dosed, is consistent.

EXEMPLARY EMBODIMENTS:

Embodiment 1

In order to investigate the flow properties and the sterility of serum eye drops, whole blood donations were carried out 5

In each case 20 ml of blood were taken. The blood was taken by means of ACD-free blood collection tubes. Appropriate

Blood collection tubes have no coagulation inhibitors (ACD: acid citrate dextrose), so that the blood in the inventive Method can be used. After blood collection, coagulation was carried out at room temperature in standing tubes. The

Coagulation was complete when the blood cake containing the solid components of the blood could be detached from the vessel wall with a spatula. This could be done after 20 to 30 minutes.

After removing the blood cake from the tubes, the serum contained therein was centrifuged at 3500 rpm for 20 minutes. Immediately thereafter, the serum supernatant was pipetted off and the resulting serum stored in the refrigerator at a temperature of 4 ° C to 8 ° C.

The serum was in administration vessels pumping system as described by the company Aero Pump GmbH as a eye dropper system with 3K ^® -

System are sold, bottled. It became the following

receive ready-to-use eye drops:

Example AT 1: 5 ml serum in the administration vessel

Example AT 2: 5 ml serum eye drops (10% dilution with

isotonic saline)

Example AT 3: 5 ml serum eye drops (20% dilution with

isotonic saline)

Example AT 4: 5 ml serum eye drops (30% dilution with

isotonic saline)

A dilution of 10% means that 90% by weight of the

Serum eye drops are serum and 10% by weight isotonic saline. The same applies to the other dilutions. The ready-to-use eye drops were stored in the refrigerator at a temperature of 4 ° C to 8 ° C. Samples were taken 5 times daily over a period of 9 days from the respective eye drops ATI to AT 4.

All samples had very good flowability and a slight pink color, which decreased with increasing dilution. The samples taken had the same volume throughout. Even after 9 days, no microbial contamination was

Eye drops visible.

Embodiment 2:

Whole blood (500 ml) was drawn into blood bags by 10 persons according to standard procedure of the DRK Blood Transfusion Service (Standard Operation Procedure). After coagulation of the blood (overnight at

Room temperature) and centrifugation (15 minutes at 3000

Revolutions / min) the serum was transferred to the blood bag

transferred welded empty bag.

The serum was transported at + 4 ° C in a clean room (class A in B). There, the filling of the serum took place in

Delivery containers with pumping system, as sold by the company Aero Pump GmbH as eye dropper system with 3K ^® system bottled. The samples were each stored differently and examined before bottling and then on their sterility:

Example AT 5: Serum before filling in the administration vessel Example AT 6: Serum in pump system after 48 h storage at -20 ° C. Example AT 7: Serum in pump system after 48 h storage at +4 ° C to +8 ° C

Example AT 8: Serum in pump system after 48 h storage at

Room temperature (20 ° C)

Example AT 9: Serum in pumping system after 5 days storage at room temperature (20 ° C)

In all examples AT 5 to AT 9 were performed

Sterile controls (tests according to the European Pharmacopoeia on aerobic and anaerobic bacteria and fungi) negative. The controls were carried out with an automated detection method BacT / Alert by Bio

Merieux, Nürtingen.

Claims

claims

1. A process for the preparation of ready-to-use eye drops comprising the following steps:

c) Examination of the serum for the presence of pathogens followed by

d) filling the serum into at least one delivery means at a second location,

where first place and second place are different from each other.

The method of claim 1, further comprising step e) final examinations prior to the release of the eye drops as drug sterility.

3. The method according to claim 1 or 2, characterized in that the whole blood is autologous or allogeneic.

4. The method according to any one of claims 1 to 3, characterized

in that the filling in step d) takes place in a clean room, in particular in a clean room in a pharmacy.

5. The method according to any one of claims 1 to 4 comprising the following steps:

a) collecting whole blood in a blood bag at a first location and then transporting the whole blood to a second location, b) separating the blood to obtain serum at the second location, bl) Transferring the serum under sterile conditions into one

Serum bag at the second place,

Pumping device for metering the eye drops into the eye.

6. The method according to any one of claims 1 to 5, characterized

characterized in that the serum is diluted before or during filling in step d).

7. The method according to claim 6, characterized in that the dilution is carried out in the range of 10% to 30%.

8. The method according to claim 6 or 7, characterized in that the dilution is carried out with known tear substitutes, in particular with isotonic saline.

9. eye drops obtainable by the method according to one of claims 1 to 8.

10. Use of eye drops according to claim 9 for the treatment of dry eye.

11. Kit comprising eye drops according to claim 9 in one

Administration container.

12. Kit according to claim 11, characterized in that the

Administration container comprises a pumping system which has a container for receiving the eye drops and a pump device for dosing the eye drops.